Novel compounds as cannabinoid receptor ligands

ABSTRACT

The present invention relates to thiophene containing compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein m, n, p, q, r, s, R 1 , R 2 , and R 3  are as defined in the description. Included also are pharmaceutical compositions comprising such compounds, and methods for treating conditions and disorders using such compounds and pharmaceutical compositions.

This application claims priority to U.S. patent application Ser. No.60/841,355, filed Aug. 31, 2006 and is incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to thiophene containing compounds,compositions comprising such compounds, and methods of treatingconditions and disorders using such compounds and compositions.

BACKGROUND

(−)-Δ⁹-Tetrahydrocannabinol (Δ⁹-THC), the major psychoactive constituentof marijuana, exerts a broad range of biological effects through itsinteractions with two cannabinoid (CB) receptor subtypes, CB₁ and CB₂.CB₁ receptors are highly expressed in the central nervous system and toa lesser degree in the periphery in a variety of tissues of thecardiovascular and gastrointestinal systems. By contrast, CB₂ receptorsare most abundantly expressed in multiple lymphoid organs and cells ofthe immune system, including spleen, thymus, tonsils, bone marrow,pancreas and mast cells.

The psychotropic effects caused by Δ⁹-THC and other nonselective CBagonists are mediated by CB₁ receptors. These CB₁ receptor-mediatedeffects, such as euphoria, sedation, hypothermia, catalepsy, andanxiety, have limited the development and clinical utility ofnonselective CB agonists. Recent studies have demonstrated that CB₂modulators are analgesic in preclinical models of nociceptive andneuropathic pain without causing the adverse side effects associatedwith CB₁ receptor activation. Therefore, compounds that selectivelytarget CB₂ receptors are an attractive approach for the development ofnovel analgesics.

Pain is the most common symptom of disease and the most frequentcomplaint with which patients present to physicians. Pain is commonlysegmented by duration (acute vs. chronic), intensity (mild, moderate,and severe), and type (nociceptive vs. neuropathic).

Nociceptive pain is the most well known type of pain, and is caused bytissue injury detected by nociceptors at the site of injury. After theinjury, the site becomes a source of ongoing pain and tenderness. Thispain and tenderness are considered “acute” nociceptive pain. This painand tenderness gradually diminish as healing progresses and disappearwhen healing is complete. Examples of acute nociceptive pain includesurgical procedures (post-op pain) and bone fractures. Even though theremay be no permanent nerve damage, “chronic” nociceptive pain resultsfrom some conditions when pain extends beyond six months. Examples ofchronic nociceptive pain include osteoarthritis, rheumatoid arthritis,and musculoskeletal conditions (e.g., back pain), cancer pain, etc.

Neuropathic pain is defined as “pain initiated or caused by a primarylesion or dysfunction in the nervous system” by the InternationalAssociation for the Study of Pain. Neuropathic pain is not associatedwith nociceptive stimulation, although the passage of nerve impulsesthat is ultimately perceived as pain by the brain is the same in bothnociceptive and neuropathic pain. The term neuropathic pain encompassesa wide range of pain syndromes of diverse etiologies. The three mostcommonly diagnosed pain types of neuropathic nature are diabeticneuropathy, cancer neuropathy, and HIV pain. In addition, neuropathicpain is diagnosed in patients with a wide range of other disorders,including trigeminal neuralgia, post-herpetic neuralgia, traumaticneuralgia, phantom limb, as well as a number of other disorders ofill-defined or unknown origin.

Managing the spectrum of pain etiologies remains a major public healthproblem and both patients and clinicians are seeking improved strategiesto effectively manage pain. No currently available therapies or drugseffectively treat all types of nociceptive and neuropathic pain states.The compounds of the present invention are novel CB₂ receptor modulatorsthat have utility in treating pain, including nociceptive andneuropathic pain.

The location of CB₂ receptors on the surface of immune cells suggests arole for these receptors in immunomodulation and inflammation. Recentstudies have demonstrated that CB₂ receptor ligands haveimmunomodulatory and anti-inflammatory properties. Therefore, compoundsthat interact with CB₂ receptors offer a unique pharmacotherapy for thetreatment of immune and inflammatory disorders.

Accordingly, the need exists to further explore and develop CB₂ receptorligands that exhibit immunomodulatory and anti-inflammatory properties.These CB₂ receptors ligands will offer a unique pharmacotherapy for thetreatment of immune and inflammatory disorders.

SUMMARY

The present invention generally provides thiophene containing compoundsand pharmaceutical compositions and methods for the treatment ofdisorders using these compounds and pharmaceutical compositions.

In one embodiment, the present invention provides compounds of formula(I), or a pharmaceutically suitable salt or prodrug thereof,

wherein

is absent or is a bond;

m, n are each independently 0, 1 or 2;

p is 1 or 2;

q and r are each independently 0 or 1;

s is 0, 1, 2, 3, or 4;

R₁ is selected from the group consisting of alkyl, alkoxyalkyl,alkylcarbonyl, cyano, cyanoalkyl, halo, haloalkyl, R₄O₂C—,R_(c)R_(d)NC(O)—, and R_(c)R_(d)NS(O)₂—;

R₂ is selected from the group consisting of aryl, cycloalkyl,heteroaryl, heterocycle, —O(R_(h)), and R_(e)R_(f)N—;

R₃ is selected from the group consisting of alkyl, alkoxyalkyl,haloalkyl, hydroxyalkyl, R₅—C(O)—, R₅—C(═N—OR_(p))—, R₆OC(O)—,R_(g)R_(j)NC(O)—, R₅—S(O)₂—, and R_(g)R_(j)NS(O)₂—;

R₄ is selected from the group consisting of alkyl, arylalkyl, haloalkyl,heteroarylalkyl, and heterocyclealkyl;

R₅, at each occurrence, is independently selected from the groupconsisting of alkyl, alkoxyalkyl, aryl, cycloalkyl, haloalkyl,heteroaryl, and heterocycle;

R₆ is selected from the group consisting of alkyl, arylalkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, heterocyclealkyl, and heteroarylalkyl;

R_(c) and R_(d), at each occurrence, are each independently selectedfrom the group consisting of hydrogen and alkyl, or R_(c) and R_(d)together with the nitrogen atom to which they are attached form aheterocyclic ring;

R_(e) is selected from the group consisting of hydrogen, alkyl,cycloalkyl, and alkylcarbonyl;

R_(f) is selected from the group consisting of hydrogen and alkyl;

R_(g), at each occurrence, is independently selected from the groupconsisting of hydrogen, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, heteroarylalkyl,heterocyclealkyl, and heterocyclealkyl;

R_(j), at each occurrence, is independently selected from the groupconsisting of hydrogen, alkyl, and haloalkyl;

R_(h) is a cycloalkyl ring optionally substituted with 1, 2, 3, 4, 5, or6 substituents independently selected from the group consisting ofalkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, haloalkyl, arylalkyl,heteroarylalkyl, cycloalkyl, and heterocyclealkyl; and

R_(p) is selected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a method fortreating pain (for example, neuropathic pain or nociceptive pain) in amammal in need of such treatment. The method comprises administering tothe mammal a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt thereof.

In yet another embodiment the present invention provides a method fortreating a disorder selected from the group consisting of inflammatorydisorders, immune disorders, neurological disorders, cancers of theimmune system, respiratory disorders, and cardiovascular disorders in amammal in need of such treatment. The method comprises administering tothe mammal a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention relates to a method forproviding neuroprotection in a mammal in need of such treatment. Themethod comprises administering to the mammal a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof the invention or a pharmaceutically acceptable salt thereof incombination with one or more pharmaceutically acceptable carriers. Thecomposition is preferably useful for the treatment of the diseaseconditions described above.

Further, the present invention provides the use of a compound of formula(I) or a pharmaceutically acceptable salt thereof, in the manufacture ofa medicament for the treatment of the disease conditions describedabove.

These and other objects of the invention are described in the followingparagraphs. These objects should not be deemed to narrow the scope ofthe invention defined by the claims.

DEFINITION OF TERMS

For a variable that occurs more than one time in any substituent or inthe compound of the invention or any other formulae herein, itsdefinition on each occurrence is independent of its definition at everyother occurrence. Combinations of substituents are permissible only ifsuch combinations result in stable compounds. Stable compounds arecompounds which can be isolated from a reaction mixture.

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkoxy” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through anotheralkoxy group, as defined herein. Representative examples of alkoxyalkoxyinclude, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy,2-methoxyethoxy, and methoxymethoxy.

The term “alkoxyalkoxyalkyl” as used herein, means an alkoxyalkoxygroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofalkoxyalkoxyalkyl include, but are not limited to,tert-butoxymethoxymethyl, ethoxymethoxymethyl, (2-methoxyethoxy)methyl,and 2-(2-methoxyethoxy)ethyl.

The term “alkoxyalkyl” as used herein, means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of alkoxyalkylinclude, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl,2-methoxyethyl, and methoxymethyl.

The term “alkoxycarbonyl” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxycarbonylalkyl” as used herein, means an alkoxycarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofalkoxycarbonylalkyl include, but are not limited to,3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and2-tert-butoxycarbonylethyl.

The term “alkoxysulfonyl” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein.

The term “alkyl” as used herein, means a straight or branched chainsaturated hydrocarbon containing from 1 to 10 carbon atoms.Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,2,3-dimethylpentyl, 1,2,2-trimethylpropyl, n-heptyl, n-octyl, n-nonyl,and n-decyl.

The term “alkylcarbonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “alkylcarbonylalkyl” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofalkylcarbonylalkyl include, but are not limited to, 2-oxopropyl,3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.

The term “alkylcarbonyloxy” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an oxygen atom. Representative examples of alkylcarbonyloxyinclude, but are not limited to, acetyloxy, ethylcarbonyloxy, andtert-butylcarbonyloxy.

The term “alkylene” means a divalent group derived from a straight orbranched chain saturated hydrocarbon of from 1 to 10 carbon atoms.Representative examples of alkylene include, but are not limited to,—CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and—CH₂CH(CH₃)CH₂—.

The term “alkylsulfinyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfinyl group, as defined herein. Representative examples ofalkylsulfinyl include, but are not limited to, methylsulfinyl andethylsulfinyl.

The term “alkylsulfinylalkyl” as used herein, means an alkylsulfinylgroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofalkylsulfinylalkyl include, but are not limited to, methylsulfinylmethyland ethylsulfinylmethyl.

The term “alkylsulfonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkylsulfonyl include, but are not limited to, methylsulfonyl andethylsulfonyl.

The term “alkylsulfonylalkyl” as used herein, means an alkylsulfonylgroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofalkylsulfonylalkyl include, but are not limited to, methylsulfonylmethyland ethylsulfonylmethyl.

The term “alkylthio” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of alkylthio include, but are not limited,methylthio, ethylthio, tert-butylthio, and hexylthio.

The term “alkylthioalkyl” as used herein, means an alkylthio group, asdefined herein, appended to the parent molecular moiety through analkylene group, as defined herein. Representative examples ofalkylthioalkyl include, but are not limited, methylthiomethyl and2-(ethylthio)ethyl.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “aryl,” as used herein, means phenyl, a bicyclic aryl or atricyclic aryl. Bicyclic aryls are exemplified by naphthyl, or a phenylfused to a monocyclic cycloalkyl, or a phenyl fused to a monocycliccycloalkenyl. Representative examples of the bicyclic aryls include, butare not limited to, dihydroindenyl, indenyl, naphthyl,dihydronaphthalenyl, and tetrahydronaphthalenyl. Tricyclic aryls areexemplied by a bicyclic aryl fused to a monocyclic cycloalkyl, or abicyclic aryl fused to a monocyclic cycloalkenyl, or a bicyclic arylfused to a phenyl. Representative examples of tricyclic aryls include,but are not limited to, anthracenyl, dihydroanthracenyl, fluorenyl, andtetrahydrophenanthrenyl. The aryl groups of the present invention areattached to the parent molecular moiety through any substitutable carbonatoms within the groups.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of arylalkyl include,but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl,1-methyl-1-phenylethyl, and 2-naphth-2-ylethyl.

The term “carbonyl” as used herein, means a —C(O)— group.

The term “carboxy” as used herein, means a —CO₂H group.

The term “carboxyalkyl” as used herein, means a carboxy group, asdefined herein, appended to the parent molecular moiety through analkylene group, as defined herein. Representative examples ofcarboxyalkyl include, but are not limited to, carboxymethyl,2-carboxyethyl, and 3-carboxypropyl.

The term “cyano” as used herein, means a —CN group.

The term “cyanoalkyl” as used herein, means a cyano group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of cyanoalkyl include,but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.

The term “cycloalkenyl” as used herein, means a monocyclic cycloalkenylor bicyclic cycloalkenyl. The monocyclic cycloalkenyls are exemplifiedby cyclic hydrocarbon groups containing from 3 to 10 carbon atoms and atleast one carbon-carbon double bond in the ring. Representative examplesof monocyclic cycloalkenyls include, but are not limited to,2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4-cyclohexadien-1-yl and3-cyclopenten-1-yl. Bicyclic cycloalkenyls are exemplified by amonocyclic cycloalkenyl fused to a monocyclic cycloalkyl ring, or amonocyclic cycloalkenyl fused to a monocyclic cycloalkenyl.Representative examples of bicyclic cycloalkenyls include, but are notlimited to, 3a, 4, 5, 6, 7,7a-hexahydro-1H-indenyl, and 1, 2, 3,4,5,6-hexahydro-pentalenyl. The cycloalkenyl groups of the presentinvention are attached to the parent molecular moiety through anysubstitutable carbon atoms within the groups.

The term “cycloalkyl” as used herein, means a monocyclic cycloalkyl, ora bicyclic cycloalkyl. Monocyclic cycloalkyls are exemplified by asaturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms.Bicyclic cycloalkyls are exemplified by a monocyclic cycloalkyl fused toa monocyclic cycloalkyl. The cycloalkyl groups of the present inventionare appended to the parent molecular moiety through any substitutablecarbon atom within the group, and may contain one or two alkylenebridges of 1, 2, 3, or 4 carbon atoms wherein each bridge links twonon-adjacent carbon atoms within the group. Representative examplescycloalkyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl(tricyclo[3.3.1.1^(3,7)]decanyl), noradamantyl(octahydro-2,5-methanopentalene), bicyclo[2.2.2]octyl,bicyclo[3.3.1]nonanyl, bicyclo[2.2.1]heptyl, and bicyclo[3.1.1]heptyl.

The term “cycloalkylalkyl” as used herein, means a cycloalkyl groupappended to the parent molecular moiety through an alkylene group, asdefined herein. Examples of cycloalkylalkyl include, but are not limitedto, cyclopropylmethyl and cyclopropyl-1-methylethyl.

The term “formyl” as used herein, means a —C(O)H group.

The term “formylalkyl” as used herein, means a formyl group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of formylalkylinclude, but are not limited to, formylmethyl and 2-formylethyl.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkoxy” as used herein, means an alkoxy group, as definedherein, in which one, two, three, four, five, or six hydrogen atoms arereplaced by halogen. Representative examples of haloalkoxy include, butare not limited to, trifluoromethoxy, difluoromethoxy,2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 2-fluoroethoxy, andpentafluoroethoxy.

The term “haloalkoxyalkyl” as used herein, means an haloalkoxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five, six, or seven hydrogenatoms are replaced by halogen. Representative examples of haloalkylinclude, but are not limited to, chloromethyl, 2-fluoroethyl,2,2,2-trifluoroethyl, trifluoromethyl, 3,3,3-trifluoropropyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “heteroaryl” as used herein, means a monocyclic heteroaryl or abicyclic heteroaryl. The monocyclic heteroaryl is a 5- or 6-memberedring containing at least one heteroatom independently selected from thegroup consisting of O, N, and S. The 5-membered ring contains two doublebonds and one, two, three or four heteroatoms in the ring. The6-membered ring contains three double bonds and one, two, three or fourheteroatoms in the ring. Representative examples of monocyclicheteroaryls include, but are not limited to, furanyl, imidazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroarylsare exemplified by a monocyclic heteroaryl fused to a phenyl, or amonocyclic heteroaryl fused to a monocyclic cycloalkyl, or a monocyclicheteroaryl fused to a monocyclic cycloalkenyl, or a monocyclicheteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroarylfused to a monocyclic heterocycle. Representative examples of bicyclicheteroaryl include, but are not limited to, benzofuranyl,benzoxadiazolyl, 1,3-benzothiazolyl, benzimidazolyl, benzodioxolyl,benzothiophenyl, chromenyl, cinnolinyl, furopyridine, indolyl,indazolyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridine,quinolinyl, thienopyridine and thienopyridinyl. The heteroaryl groups ofthe present invention are appended to the parent molecular moietythrough a substitutable atom within the groups.

The term “heteroarylalkyl” as used herein, means a heteroaryl groupappended to the parent molecular moiety through an alkylene group, asdefined herein.

The term “heterocycle” or “heterocyclic” as used herein, refers to amonocyclic heterocycle, a bicyclic heterocycle, or a tricyclicheterocycle containing at least one heteroatom. The monocyclicheterocycle is a 3-, 4-, 5-, 6-, 7, or 8-membered ring containing atleast one heteroatom independently selected from the group consisting ofO, N, and S. The 3- or 4-membered ring contains zero double bond and 1heteroatom selected from the group consisting of O, N and S. The5-membered ring contains zero or one double bond and one, two or threeheteroatoms selected from the group consisting of O, N and S. The 6-,7-, or 8-membered ring contains zero, one or two double bonds and one,two or three heteroatoms selected from the group consisting of O, N andS. Representative examples of monocyclic heterocycle include, but arenot limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl,3,4-dihydro-2H-pyranyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl,thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl,thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone),thiopyranyl, and trithianyl. The bicyclic heterocycles of the presentinvention are exemplified by a monocyclic heterocycle fused to a phenylgroup, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, ora monocyclic heterocycle fused to a cycloalkenyl, or a monocyclicheterocycle fused to a monocyclic heterocycle. Representative examplesof bicyclic heterocycles include, but are not limited to,1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-1,4-benzodioxinyl,2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl,2,3-dihydro-1H-indolyl, and 1,2,3,4-tetrahydroquinolinyl. The tricyclicheterocycle is a bicyclic heterocycle fused to a phenyl, or a bicyclicheterocycle fused to a monocyclic cycloalkyl, or a bicyclic heterocyclefused to a monocyclic cycloalkenyl, or a bicyclic heterocycle fused to amonocyclic heterocycle. Representative examples of tricyclicheterocycles include, but are not limited to,2,3,4,4a,9,9a-hexahydro-1H-carbazolyl,5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furanyl, and5a,6,7,8,9,9a-hexahydrodibenzo[b,d]thienyl. The heterocycle groups ofthe present invention are connected to the parent molecular moietythrough any substitutable carbon atom or any substitutable nitrogen atomcontained within the groups, and may contain one or two alkylene bridgesof 1, 2, 3, or 4 carbon atoms, each linking two non-adjacent carbonatoms of the group. Examples of such bridged heterocycle groups include,but are not limited to, 2-oxatricyclo[3.3.1.1^(3,7)]decanyl,2,4-dioxabicyclo[4.2.1]nonanyl, and oxabicyclo[2.2.1]heptyl.

The term “heterocyclealkyl” as used herein, means a heterocycle groupappended to the parent molecular moiety through an alkylene group, asdefined herein. Non-limiting example heterocyclealkyl includestetrahydrofuranylmethyl.

The aryl, cycloalkyl, cycloalkenyl, heterocycle, and the heteroarylgroups of the present invention, as a substituent or part of asubstituent, are each independently unsubstituted or substituted with 1,2, 3, 4, 5 or 6 substituents, R₁₀₁, unless otherwise noted. Each R₁₀₁ isindependently selected from the group consisting of alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl,alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfinylalkyl,alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl,carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen,haloalkoxy, haloalkoxyalkyl, haloalkyl, hydroxy, hydroxyalkyl, mercapto,nitro, oxo, —NZ₁Z₂ and (NZ₃Z₄)carbonyl.

The term “hydroxy” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein, means at least one hydroxygroup, as defined herein, is appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypentyl,and 2-ethyl-4-hydroxyheptyl.

The term “mercapto” as used herein, means a —SH group. The term “nitro”as used herein, means a —NO₂ group. The term “NZ₁Z₂” as used herein,means two groups, Z₁ and Z₂, which are appended to the parent molecularmoiety through a nitrogen atom. Z₁ and Z₂ are each independentlyhydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl and formyl. In certaininstances within the present invention, Z₁ and Z₂ taken together withthe nitrogen atom to which they are attached form a heterocyclic ring.Representative examples of NZ₁Z₂ include, but are not limited to, amino,methylamino, acetylamino, acetylmethylamino, phenylamino, benzylamino,azetidinyl, pyrrolidinyl and piperidinyl.

The term “NZ₃Z₄” as used herein, means two groups, Z₃ and Z₄, which areappended to the parent molecular moiety through a nitrogen atom. Z₃ andZ₄ are each independently hydrogen, alkyl, aryl, and arylalkyl.Representative examples of NZ₃Z₄ include, but are not limited to, amino,methylamino, phenylamino and benzylamino.

The term “(NZ₃Z₄)carbonyl” as used herein, means a NZ₃Z₄ group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples of(NZ₃Z₄)carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

The term “oxo” as used herein, means a ═O moiety.

The term “sulfinyl” as used herein, means a —S(O)— group.

The term “sulfonyl” as used herein, means a —SO₂— group.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary, but are notrestrictive, of the invention.

DETAILED DESCRIPTION

Compounds of the invention have the formula (I) as described above.Examples of compounds of formula (I) include those wherein m is 0, n is1, p is 1, q is 0, r is 0, and - - - is absent. Other examples ofcompounds disclosed of formula (I) include those wherein m is 1, n is 0,p is 1, q is 0, r is 0, and

is absent. Yet other examples of compounds of formula (I) include thosewherein m is 0, n is 0, p is 1, q is 0, r is 0, and

is absent.

It is to be understood that when m is 0, n is 1, p is 1, q is 0, r is 0,and - - - is absent in formula (I), this refers to compounds of formula(Ia)

when m is 1, n is 0, p is 1, q is 0, r is 0, and

is absent in formula (I), this refers to compounds of formula (Ib)

and when m is 0, n is 0, p is 1, q is 0, r is 0, and

is absent in formula (I), this refers to compounds of formula (Ic)

Within each group of examples described hereinabove, s, R₁, R₂, and R₃have the meanings as defined in the summary section.

Within each group of compounds of formula (I) as described in thepreceding paragraphs, examples of a subgroup include those wherein R₃ isalkyl, alkoxyalkyl, haloalkyl, or hydroxyalkyl.

Other examples of a subgroup include those wherein R₃ is R₅—C(O)— and R₅is as defined in the summary section. For example, R₅ is cycloalkyl(such as, but not limited to, cyclobutyl), heteroaryl (such as, but notlimited to, furanyl), or heterocycle (such as, but not limited to,azetidinyl), wherein each of these rings is independently unsubstitutedor substituted as described in the Definition of Terms section. Examplesof the optional substituents include, but are not limited to, alkyl,haloalkyl, halogen, and alkoxy.

Other examples of a subgroup include compounds of formula (I) wherein R₃is R₅—C(═N—OR_(p))—, and R₅ and R_(p) are as disclosed in the summary.

Further examples of a subgroup include compounds of formula (I) whereinR₃ is R₆OC(O)— and R₆ is as disclosed in the summary section. Forexample, R₆ is C₁₋₆ alkyl. In one embodiment R₆ is C₁₋₃ alkyl. In yetanother embodiment, R₆ is ethyl or n-propyl.

Yet further examples of a subgroup include compounds of formula (I)wherein R₃ is R₅—S(O)₂— or R_(g)R_(j)NS(O)₂—, and R₅, R_(g), and R_(j)are as defined in the summary section.

Yet other examples of a subgroup include compounds of formula (I)wherein R₃ is R_(g)R_(j)NC(O)—; and R_(g) and R_(j) are as disclosed inthe summary section. For example, R_(g) is alkyl (such as methyl, ethyl,n-propyl, and the like), alkoxyalkyl (e.g. 2-methoxyethyl), cycloalkyl(e.g. cyclobutyl, cyclopentyl, and the like), haloalkyl (e.g.2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and the like), hydroxyalkyl(e.g. 2-hydroxyethyl and the like), or heterocyclealkyl (e.g.tetrahydrofuranylmethyl, and the like). R_(j) is, for example, hydrogenor methyl.

Of all the groups and subgroups of compounds of formula (I) as describedin the preceding paragraphs, one embodiment is directed to compounds offormula (I) wherein R₂ is aryl, cycloalkyl, or heteroaryl, each of whichis independently unsubstituted or substituted as described in theDefinition of Terms. For example, R₂ is unsubstituted or substitutedphenyl. Further examples of R₂ are cyclopropyl andoctahydro-2,5-methanopentalene, each of which is independentlyunsubstituted or substituted. Yet another example of R₂ is unsubstitutedor substituted isoquinolinyl. Examples of the optional substituents ofR₂ include, but are not limited to, alkoxy (e.g. methoxy, ethoxy, andthe like), alkyl (e.g. methyl, isopropyl, and the like), halogen(fluoro, chloro, and the like), haloalkyl (e.g. trifluoromethyl, and thelike), and haloalkoxy (e.g. trifluoromethoxy, and the like). Anotherembodiment is directed to compounds of formula (I) wherein R₂ is—O(R_(h)) or NR_(e)R_(f), and R_(h), R_(e) and R_(f) are as disclosed inthe summary section. For example R₂ is —O(cyclohexyl) wherein thecyclohexyl moiety is optionally substituted as described in the summarysection. Examples of R_(e) include, but are not limited to, alkyl (e.g.1,1-dimethylpropyl, 1,2,2-trimethylpropyl, 1,2-dimethylpropyl, and thelike) and cycloalkyl (e.g. cyclopentyl). R_(f) is, for example,hydrogen.

Representative examples of compounds of formula (I) include, but are notlimited to:

-   ethyl    2-{[(2,2,3,3-tetramethylcyclopropyl)carbonyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate;-   ethyl    2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate;-   ethyl    2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate;-   N-{3-[(3,3-difluoroazetidin-1-yl)carbonyl]-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl}-2-fluoro-6-(trifluoromethyl)benzamide;-   N-[3-(azetidin-1-ylcarbonyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl]-2-fluoro-6-(trifluoromethyl)benzamide;-   2-fluoro-N-{3-[(3-methoxyazetidin-1-yl)carbonyl]-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl}-6-(trifluoromethyl)benzamide;-   2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-N-propyl-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide;-   N-[3-(cyclobutylcarbonyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl]-2-fluoro-6-(trifluoromethyl)benzamide;-   N-cyclobutyl-2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide;-   N-cyclopentyl-2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide;-   2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-N-(2-methoxyethyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide;-   2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-N-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide;-   2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-N-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide;-   2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-N-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide;-   2-fluoro-N-[3-(2-furoyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl]-6-(trifluoromethyl)benzamide;-   N-[3-(cyclobutylcarbonyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl]-N′-(1,1-dimethylpropyl)urea;-   N-[3-(cyclobutylcarbonyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl]-N′-cyclopentylurea;-   N-[3-(cyclobutylcarbonyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl]-N′-(1,2,2-trimethylpropyl)urea;-   ethyl    2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thiophene-3-carboxylate;-   N-[3-(cyclobutylcarbonyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl]-N′-(1,2-dimethylpropyl)urea;-   ethyl    2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thiophene-3-carboxylate;-   N-{3-[(3,3-difluoroazetidin-1-yl)carbonyl]-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thien-2-yl}-2-fluoro-6-(trifluoromethyl)benzamide;-   2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-N-propyl-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thiophene-3-carboxamide;-   N-{3-[(3,3-difluoroazetidin-1-yl)carbonyl]-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thien-2-yl}hexahydro-2,5-methanopentalene-3a(1H)-carboxamide;-   ethyl    2-[({[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy}carbonyl)amino]-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate;-   ethyl    2-{[5-chloro-2-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate;-   ethyl    2-{[3-chloro-2-fluoro-6-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate;-   2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-propyl-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thiophene-3-carboxamide;-   2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thiophene-3-carboxamide;-   ethyl    2-[(isoquinolin-1-ylcarbonyl)amino]-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate;-   2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-N-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide;-   N-ethyl-2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide;-   N-cyclopentyl-2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thiophene-3-carboxamide;-   propyl    2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate;-   2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-N,N-dimethyl-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide;-   N-{3-[(3-methoxyazetidin-1-yl)carbonyl]-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thien-2-yl}hexahydro-2,5-methanopentalene-3a(1H)-carboxamide;-   ethyl    2-[({[(1R,2S,5R)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyl]oxy}-carbonyl)amino]-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate;-   propyl    2-{[2-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate;    and-   ethyl    2-{[2-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate.

Compounds of the present invention may exist as stereoisomers whereinasymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralcarbon atom. The terms “R” and “S” used herein are configurations asdefined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The presentinvention contemplates various stereoisomers (including enantiomers anddiastereomers) and mixtures thereof. Individual stereoisomers ofcompounds of the present invention may be prepared synthetically fromcommercially available starting materials that contain asymmetric orchiral centers or by preparation of racemic mixtures followed byresolution of the individual stereoisomer using methods that are knownto those of ordinary skill in the art. Examples of resolution are, forexample, (i) attachment of a mixture of enantiomers to a chiralauxiliary, separation of the resulting mixture of diastereomers byrecrystallization or chromatography, followed by liberation of theoptically pure product; or (ii) separation of the mixture of enantiomersor diastereomers on chiral chromatographic columns.

Geometric isomers may exist in the present compounds. The inventioncontemplates the various geometric isomers and mixtures thereofresulting from the disposition of substituents around a carbon-carbondouble bond, a carbon-nitrogen double bond, a cycloalkyl group, or aheterocycle group. Substituents around a carbon-carbon double bond or acarbon-nitrogen bond are designated as being of Z or E configuration andsubstituents around a cycloalkyl or a heterocycle are designated asbeing of cis or trans configuration.

Within the present invention it is to be understood that compoundsdisclosed hererin may exhibit the phenomenon of tautomerism.

Thus, the formulae drawings within this specification can represent onlyone of the possible tautomeric or stereoisomeric forms. It is to beunderstood that the invention encompasses any tautomeric orstereoisomeric form, and mixtures thereof, and is not to be limitedmerely to any one tautomeric or stereoisomeric form utilized within thenaming of the compounds or formulae drawings.

Abbreviations

Abbreviations which have been used in the descriptions of the Schemesand the Examples that follow are: DMSO for dimethylsulfoxide; and HOBtfor 1-hydroxybenzotriazole hydrate.

Methods for Preparing Compounds

This invention is intended to encompass compounds of the invention whenprepared by synthetic processes or by metabolic processes. Preparationof the compounds by metabolic processes includes those occurring in thehuman or animal body (in vivo) or processes occurring in vitro.

The compounds of the invention may be prepared by a variety of processeswell known for the preparation of compounds of this class. For example,the compounds of the invention wherein the groups R_(e), R_(f), R_(g),R_(j), R₁, R₂, R₃, R₅, R₆, m, n, p, q, r, and s have the meanings as setforth in the summary section unless otherwise noted, can be synthesizedas shown in Schemes 1-7.

As shown in Scheme 1, compounds of formula (I) can be prepared bytreating compounds of formula (1) with compounds of formula (2) whereinX is chloro or —OH under appropriate conditions. For example, compoundsof formula (I) can be obtained by stirring an about equimolar mixture ofthe compounds of formula (2) wherein X is chloro, and compounds offormula (1) in solvents such as chloroform, dichloromethane ortetrahydrofuran, in the presence of a base such as, but not limited to,diisopropylethylamine and at a temperature of about 0° C. to about 40°C. Alternatively, compounds of formula (I) can be prepared by stirringan equimolar mixture of compounds of formula (2) wherein X is —OH andcompounds of formula (1), a coupling reagent, optionally a couplingauxillry, and optionally a base, in a solvent such as, but not limitedto, tetrahydrofuran, N,N-dimethylacetamide, N,N-dimethylformamide,dichloromethane, ethyl acetate, or mixtures thereof. Non-limitingexamples of coupling reagents are 1,1′-carbonyldiimidazole (CDI),bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPC1),1,3-dicyclohexylcarbodiimide (DCC), polymer supported1,3-dicyclohexylcarbodiimide (PS-DCC),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU). Non-limiting examples of coupling auxiliary are1-hydroxy-7-azabenzotriazole (HOAT) and 1-hydroxybenzotriazole hydrate(HOBT). Examples of suitable base include, but are not limited toN-methyl morpholine, diisopropylethylamine, pyridine, and the like. Thecoupling1 reactions can be carried out, for example, at a temperaturebetween about 0° C. to about 65° C., and optionally in a microwavereactor.

Compounds of formula (I) wherein R₂ is R_(e)R_(f)N— can be preparedusing general procedures as outlined in Schemes 2-4.

Compounds of formula (1) when treated with triphosgene of formula (4) inthe presence of a base, followed by addition of an amine of formula (5)provide compounds of formula (6). Examples of suitable bases include,but are not limited to, triethylamine and diisopropylethylamine

Compounds of formula (6) can be prepared from compounds of formula (1)by (a) treating with 1,1′-carbonyldiimidazole, followed by treatmentwith methyl iodide, and (b) treating the product from step (a) with anamine of formula (5).

Compounds of formula (6) can also be obtained from (a) reactingcompounds of formula (8) with an amine of formula (5), and (b) treatingproduct from step (a) with compounds of formula (1).

Compounds of formula (I) wherein R₂ is NR_(e)R_(f) and R_(f) is hydrogencan be synthesized using general procedures as shown in Scheme 5

Compounds of formula (1) when treated with an isocyanate of formula (10)provide compounds of formula (11).

As outlined in Scheme 6, compounds of formula (12) can be hydrolyzed tothe corresponding carboxylic acids of formula (13) using reactionconditions known to one skilled in the art. For example, treatment ofcompounds of formula (12) with sodium, lithium or potassium hydroxide inan aqueous alcoholic solvent such as but not limited to aqueous methanolor ethanol, provide acids of formula (13). Reaction of compounds offormula (13) with amines of formula (14) can be achieved by usingreaction conditions as described in Scheme 1.

As shown in Scheme 7, compounds of formula (1) wherein R₃ is R₅C(O)—,R₆₀—C(O)—, R_(g)R_(j)NC(O)—, R₅S(O)₂— or R_(g)R_(j)NS(O)₂—,respectively, can be prepared from a Gewald reaction involving thecondensation of compounds of formula (16) with compounds of formula(17), (18), (19), (20) or (21), and elemental sulfur, in the presence ofabout 0.5 to about 1 equivalent of an amine base. The Gewald reaction istypically carried out in a solvent such as, but are not limited to,ethanol, N,N-dimethylformamide or dioxane, at ambient or at elevatedtemperature. Suitable examples of the amines include, but are notlimited to, diethylamine, morpholine or triethylamine A further reviewof the chemistry describing the Gewald reaction can be found in J.Heterocyclic Chem., 1999, 36, 333-345, Sabnis, R. W.; Rangnekar, D. W.;Sonawane, N. D.

It will be appreciated that the synthetic schemes and specific examplesas illustrated in the Examples section are illustrative and are not tobe read as limiting the scope of the invention as it is defined in theappended claims. All alternatives, modifications, and equivalents of thesynthetic methods and specific examples are included within the scope ofthe claims.

Optimum reaction conditions and reaction times for each individual stepmay vary depending on the particular reactants employed and substituentspresent in the reactants used. Unless otherwise specified, solvents,temperatures and other reaction conditions may be readily selected byone of ordinary skill in the art. Specific procedures are provided inthe Examples section. Reactions may be worked up in the conventionalmanner, e.g. by eliminating the solvent from the residue and furtherpurified according to methodologies generally known in the art such as,but not limited to, crystallization, distillation, extraction,trituration and chromatography. Unless otherwise described, the startingmaterials and reagents are either commercially available or may beprepared by one skilled in the art from commercially available materialsusing methods described in the chemical literature.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that may not be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the method are included in the scope of theinvention. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which maybe found in T. Greene and P. Wuts, Protecting Groups in ChemicalSynthesis (3^(rd) ed.), John Wiley & Sons, NY (1999), which isincorporated herein by reference in its entirety. Synthesis of thecompounds of the invention may be accomplished by methods analogous tothose described in the synthetic schemes described hereinabove and inspecific examples.

Starting materials, if not commercially available, may be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound of the invention isrequired, it may be obtained by carrying out one of the proceduresdescribed herein using an optically active starting material (prepared,for example, by asymmetric induction of a suitable reaction step), or byresolution of a mixture of the stereoisomers of the compound orintermediates using a standard procedure (such as chromatographicseparation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound of the inventionis required, it may be obtained by carrying out one of the aboveprocedures using a pure geometric isomer as a starting material, or byresolution of a mixture of the geometric isomers of the compound orintermediates using a standard procedure such as chromatographicseparation.

Following Examples may be used for illustrative purposes and should notbe deemed to narrow the scope of the invention.

EXAMPLES Example 1 ethyl2-{[(2,2,3,3-tetramethylcyclopropyl)carbonyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylateExample 1A 8-Oxa-bicyclo[3.2.1]octan-3-one.

The title compound was prepared according to literature methodsdescribed by Ansell, M. F. and Mason, J. S. J. Chem. Soc., Perkin Trans.I 1984, 1061-1068.

Example 1B4-Amino-11-oxa-3-thia-tricyclo[6.2.1.0^(2,6)]undeca-2(6),4-diene-5-carboxylicacid ethyl ester.

To a 50-mL, round-bottomed flask containing a magnetic stir bar wereadded Example 1A (378 mg, 3.00 mmol), ethyl cyanoacetate (373 mg, 352μL, 3.30 mmol), and sulfur powder (106 mg, 3.30 mmol). Absolute ethanol(10 mL) was added to form a slurry, and morpholine (393 mg, 393 mL, 4.50mmol) was added. A reflux condenser with N₂ inlet was attached and aheating mantle was applied. The mixture was heated to 60° C. and stirredfor 72 hours. The reaction was monitored by LC-MS. After cooling to roomtemperature, the solvent/volatiles were removed under reduced pressureto provide a brown oil. The product was purified by flash chromatography(silica gel eluting with 25% ethyl acetate in hexanes) to provide thetitle compound. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.23 (t, J=7.1 Hz, 3H),1.55-1.65 (m, 1H), 1.88-1.96 (m, 2H), 1.96-2.10 (m, 1H), 2.42 (J=17.3Hz, 1H), 2.96 (dd, J=17.1, 4.9 Hz, 1H), 4.13 (q, J=7.1 Hz, 2H),4.57-4.62 (m, 1H), 4.81-4.83 (m, 1H), 7.22 (br s, 2H). MS (ESI⁺) m/z 254(M+H)⁺.

Example 1C ethyl2-{[(2,2,3,3-tetramethylcyclopropyl)carbonyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate

To a 20-mL scintillation vial containing a magnetic stir bar were addedExample 1B (50 mg, 0.20 mmol), anhydrous tetrahydrofuran (2 mL), andtriethylamine (101 mg, 139 μL, 1.00 mmol).2,2,3,3-Tetramethyl-cyclopropanecarbonyl chloride (48 mg, 0.30 mmol)(prepared from commercially available2,2,3,3-tetramethyl-cyclopropanecarboxylic acid and thionyl chloride)was dissolved in a few drops of anhydrous tetrahydrofuran and added tothe mixture. A fine white precipitate formed immediately. The mixturewas stirred at room temperature overnight. The reaction was monitored byLC-MS. A saturated sodium bicarbonate solution (10 mL) was added and themixture was extracted with dichloromethane (3×8 mL). The combinedorganic extracts were dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to provide a brown oil. The productwas purified by flash chromatrography (silica gel 25% ethyl acetate inhexanes) to provide the title compound. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.20(br s, 6H), 1.21 (s, 3H), 1.23 (s, 3H), 1.31 (t, J=7.1 Hz, 3H), 1.53 (s,1H), 1.55-1.65 (m, 1H), 1.93-2.11 (m, 3H), 2.54 (d, J=17.1 Hz, 1H), 3.07(dd, J=17.1, 4.9 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 4.65-4.69 (m, 1H),5.04 (d, J=4.1 Hz, 1H), 11.03 (s, 1H). MS (ESI⁺) m/z 378 (M+H)⁺. Anal.calcd. for C₂₀H₂₇NO₄S: C, 63.63; H, 7.21; N, 3.71. Found: C, 63.80; H,6.93; N, 3.35.

Example 2 ethyl2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate

The title compound was prepared according to the procedure outlined inExample 1C, substituting 2-fluoro-6-trifluoromethyl-benzoyl chloride for2,2,3,3-tetramethyl-cyclopropanecarbonyl chloride. ¹H NMR (DMSO-d₆, 300MHz) δ1.26 (t, J=7.1 Hz, 3H), 1.61-1.70 (m, 1H), 1.98-2.14 (m, 3H), 2.57(d, J=17.3 HZ, 1H), 3.09 (dd, J=17.3, 4.8 Hz, 1H), 4.22 (q, J=7.1 Hz,2H), 4.68-4.72 (m, 1H), 5.13-5.15 (m, 1H), 7.73-7.86 (m, 3H), 11.51 (s,1H). MS (ESI⁺) m/z 444 (M+H)⁺. Anal. calcd. for C₂₀H₁₇F₄NO₄S: C, 54.17;H, 3.86; N; 3.16. Found: C, 54.17; H, 3.78; N, 3.13.

Example 3 ethyl2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate

The title compound was prepared according to the procedure outlined inExample 1C, substituting noradamantane-3-carbonyl chloride (preparedfrom commercially available 3-noradamantane carboxylic acid and thionylchloride) for 2,2,3,3-tetramethyl-cyclopropanecarbonyl chloride. ¹H NMR(DMSO-d₆, 300 MHz) δ 1.30 (t, J=7.1 Hz, 3H), 1.58-1.68 (m, 5H),1.77-2.10 (m, 9H), 2.34 (br s, 2H), 2.56 (d, J=17.0 Hz, 1H), 2.64 (t,J=6.6 Hz, 1H), 3.08 (dd, J=17.1, 4.9 Hz, 1H), 4.28 (q, J=7.1 Hz, 2H),4.66-4.70 (m, 1H), 5.09 (d, J=4.4 Hz, 1H), 11.27 (s, 1H). MS (ESI⁺) m/z402 (M+H)⁺.

Example 4N-{3-[(3,3-difluoroazetidin-1-yl)carbonyl]-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl}-2-fluoro-6-(trifluoromethyl)benzamideExample 4A4-(2-Fluoro-6-trifluoromethyl-benzoylamino)-11-oxa-3-thia-tricyclo[6.2.1.0^(2,6)]undeca-2(6),4-diene-5-carboxylicacid

To a 50-mL, round-bottomed flask containing a magnetic stir bar wereadded Example 2 (554 mg, 1.25 mmol), solid potassium hydroxide pellets(526 mg, 9.38 mmol), and 8 mL of 5:1 ethanol:water. A reflux condenserwas attached and a heating mantle was applied. The mixture was heated toreflux and stirred for 1.5 hours. The reaction was monitored by LC-MS.After cooling to room temperature, 1 N aqueous HCl was added to adjustedthe pH to 1 and a white precipitate formed. The mixture was extractedwith ethyl acetate. The combined organic extracts were dried overmagnesium sulfate, filtered, and

concentrated under reduced pressure. The residue was washed with ethylacetate/hexanes to provide the title compound which was used withoutfurther purification. LC-MS (ESI⁺) m/z 416 (M+H)⁺.

Example 4BN-{3-[(3,3-difluoroazetidin-1-yl)carbonyl]-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl}-2-fluoro-6-(trifluoromethyl)benzamide

To a 20-mL scintillation vial containing a magnetic stir bar were addedExample 4A (83 mg, 0.20 mmol), hydroxybenzotriazole (58 mg, 0.30 mmol),and commercially available 3,3-difluoroazetidine hydrochloride (52 mg,0.40 mmol). Anhydrous dimethylformamide (2 mL) and ethyldiisopropylamine(52 mg, 70 mL, 0.40 mmol) were added. Solid(3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (58 mg, 0.30mmol) was added and the mixture stirred at room temperature overnight.The reaction was monitored by LC-MS. The solvent/volatiles were removedunder reduced pressure. The residue was purified by flash chromatography(silica gel 30% ethyl acetate in hexanes) to provide the title compound.¹NMR (DMSO-d₆, 300 MHz) δ 1.62-1.70 (m, 1H), 1.98-2.14 (m, 3H), 2.29(J=16.3 Hz, 1H), 2.92 (dd, J=16.4, 4.9 Hz, 1H), 4.35 (t, J=12.6 Hz, 4H),4.66-4.70 (m, 1H), 5.10-5.12 (m, 1H), 7.71-7.83 (m, 3H), 11.71 (s, 1H).MS (ESI⁺) m/z 491 (M+H)⁺. Anal. calcd. for C₂₁H₁₆F₆N₂O₃S: C, 51.43; H,3.29; N, 5.71. Found: C, 50.99; H, 2.98; N, 5.57.

Example 5N-[3-(azetidin-1-ylcarbonyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl]-2-fluoro-6-(trifluoromethyl)benzamide

The title compound was prepared according to the procedure outlined inExample 4B, substituting commercially available azetidine hydrochloridefor 3,3-difluoroazetidine hydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ1.57-1.67 (m, 1H), 1.98-2.21 (m, 5H), 2.25 (d, J=16.3 Hz, 1H), 2.88 (dd,J=16.8, 4.9 Hz, 1H), 3.91 (t, J=7.6 Hz, 4H), 4.65-4.69 (m, 1H),5.08-5.10 (m, 1H), 7.70-7.82 (m, 3H), 11.84 (s, 1H); MS (ESI⁺) m/z 455(M+H)⁺. Anal. calcd. for C₂₁H₁₄F₄N₂O₃S: C, 55.50; H, 3.99; N, 6.16.Found: C, 55.38; H, 3.84; N, 6.14.

Example 62-fluoro-N-[3-[(3-methoxyazetidin-1-yl)carbonyl]-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl]-6-(trifluoromethyl)benzamide

The title compound was prepared according to the procedure outlined inExample 4B, substituting commercially available 3-methoxyazetidinehydrochloride for 3,3-difluoroazetidine hydrochloride. ¹H NMR (DMSO-d₆,300 MHz) δ 1.58-1.67 (m, 1H), 1.97-2.14 (m, 3H), 2.24 (d, J=16.3 Hz,1H), 2.88 (dd, J=16.4, 4.9 Hz, 1H), 3.18 (s, 3H), 3.74 (dd, J=10.0, 3.9Hz, 2H), 4.01-4.10 (m, 2H), 4.14-4.21 (m, 1H), 4.65-4.69 (m, 1H),5.09-5.10 (m, 1H), 7.70-7.82 (m, 3H), 11.64 (s, 1H). MS (ESI⁺) m/z 485(M+H)⁺. Anal. calcd. for C₂₂H₂₀F₄N₂O₄S: C, 54.54; H, 4.16; N, 5.78.Found: C, 54.44; H, 4.17; N, 6.00.

Example 72-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-N-propyl-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide

The title compound was prepared according to the procedure outlined inExample 4B, substituting commercially available propylamine for3,3-difluoroazetidine hydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 0.85(t, J=7.3 Hz, 3H), 1.42-1.54 (m, 2H), 1.65-1.73 (m, 1H), 1.98-2.13 (m,3H), 2.43 (d, J=15.9 Hz, 1H), 3.05-3.27 (m, 4H), 4.70-4.74 (m, 1H),5.13-5.14 (m, 1H), 7.59 (t, J=5.6 Hz, 1H), 7.71-7.84 (m, 3H), 11.88 (s,1H); MS (ESI⁺) m/z 457 (M+H)⁺.

Example 8N-[3-(cyclobutylcarbonyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl]-2-fluoro-6-(trifluoromethyl)benzamideExample 8A(2-amino-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-3-yl)(cyclobutyl)methanone

The title compound was prepared from 3-cyclobutyl-3-oxopropanenitrile(prepared by the method described in Dorsch, J. B.; McElvain, S. M. J.Am. Chem. Soc. 1932, 54, 2960-2964) and 8-oxabicyclo[3.2.1]octan-3-one(Example 1A) using the procedure described for Example 1B.

LC/MS (ESI⁺) m/z 264 (M+H)⁺.

Example 8BN-[3-(cyclobutylcarbonyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl]-2-fluoro-6-(trifluoromethyl)benzamide

The title compound was prepared from Example 8A and commerciallyavailable 2-fluoro-6-trifluoromethyl-benzoyl chloride according to theprocedure described for Example 1C. ¹H NMR (DMSO-d₆, 300 MHz) δ1.65-2.27 (m, 9H), 2.57 (d, J=16.3 Hz, 1H), 3.10-3.27 (m, 2H), 3.76-3.86(m, 1H), 4.71-4.75 (m, 1H), 5.14-5.16 (m, 1H), 7.76-7.89 (m, 3H), 12.43(br s, 1H).; MS (ESI⁺) m/z 454 (M+H)⁺. Anal. calcd. for C₂₂H₁₉F₄NO₃S: C,58.27; H, 4.22; N, 3.09. Found: C, 58.02; H, 4.06; N, 3.07.

Example 9N-cyclobutyl-2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide

The title compound was prepared from Example 4A and commerciallyavailable cyclobutylamine according to the procedure described forExample 4B. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.56-1.73 (m, 3H), 1.94-2.21 (m,8H), 2.41 (d, J=15.9 Hz, 1H), 3.21 (dd, J=16.9, 5.1 Hz, 1H), 4.24-4.37(m, 1H), 4.70-4.74 (m, 1H), 5.12-5.13 (m, 1H), 7.69-7.83 (m, 3H), 11.72(br s, 1H); MS (ESI⁺) m/z 469 (M+H)⁺. Anal. calcd. for C₂₂H₂₀F₄N₂O₃S: C,56.40; H, 4.30; N, 5.98. Found: C, 56.32; H, 4.32; N, 5.99.

Example 10N-cyclopentyl-2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide

The title compound was prepared from Example 4A and commerciallyavailable cyclopentylamine according to the procedure described forExample 4B. ¹H NMR (DMSO-d₆, 300 MHz) δ1.45-1.86 (m, 9H), 1.96-2.06 (m,3H), 2.37 (d, J=15.9 Hz, 1H), 3.18 (dd, J=15.9, 5.4 Hz, 1H), 4.09-4.16(m, 1H), 4.68-4.73 (m, 1H), 5.12-5.13 (m, 1H), 7.54 (d, J=7.1 Hz, 1H),7.70-7.83 (m, 3H), 11.68 (br s, 1H); MS (ESI⁺) m/z 483 (M+H)⁺.

Example 112-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-N-(2-methoxyethyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide

The title compound was prepared from Example 4A and commerciallyavailable 2-methoxyethylamine according to the procedure described forExample 4B. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.64-1.72 (m, 1H), 1.98-2.13 (m,3H), 2.42 (d, J=15.9 Hz, 1H), 3.17 (dd, J=16.4, 5.3 Hz, 1H), 3.23 (s,3H), 3.36-3.34 (m, 4H), 4.70-4.74 (m, 1H), 5.13-5.14 (m, 1H), 7.60 (t,J=5.3 Hz, 1H), 7.72-7.84 (m, 3H), 11.86 (br s, 1H).; MS (ESI⁺) m/z 473(M+H)⁺.

Example 122-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-N-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide

The title compound was prepared from Example 4A and commerciallyavailable 2,2,2-trifluoroethylamine hydrochloride according to theprocedure described for Example 4B. ¹H NMR (DMSO-d₆, 300 MHz) δ1.65-1.73 (m, 1H), 1.99-2.14 (m, 3H), 2.36 (d, J=15.9 Hz, 1H), 3.14 (dd,J=15.9, 4.8 Hz, 1H), 3.83-4.17 (m, 2H), 4.71-4.75 (m, 1H), 5.14-5.15 (m,1H), 7.69-7.83 (m, 3H), 8.38 (t, J=6.4 Hz, 1H), 11.58 (br s, 1H); MS(ESI⁺) m/z 487 (M+H)⁺. Anal. calcd. for C₂₀H₁₅F₇N₂O₃S: C, 48.39; H,3.05; N, 5.64. Found: C, 48.06; H, 2.77; N, 5.75.

Example 132-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-N-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide

The title compound was prepared from Example 4A and commerciallyavailable (R)-aminomethyl-2-tetrahydr according to the proceduredescribed for Example 4B. ¹H NMR (CDCl₃, 300 MHz) δ 1.52-1.61 (m, 3H),1.70-1.79 (m, 1H), 1.87-2.06 (m, 2H), 2.13-2.27 (m, 2H), 2.49 (dd,J=18.3, 14.6 Hz, 1H), 3.21-3.49 (m, 2H), 3.64-3.72 (m, 1H), 3.74-3.82(m, 1H), 3.84-3.91 (m, 1H), 3.95-4.07 (m, 1H), 4.83-4.88 (m, 1H),5.12-5.13 (m, 1H), 6.25-6.31 (m, 1H), 7.34-7.40 (m, 1H), 7.53-7.61 (m,2H), 12.61 (br s, 1H); MS (ESI⁺) m/z 499 (M+H)⁺. Anal. calcd. forC₂₃H₂₂F₄N₂O₄S: C, 55.42; H, 4.45; N, 5.62. Found: C, 55.25; H, 4.32; N,5.56.

Example 142-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-N-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide

The title compound was prepared from Example 4A and commerciallyavailable (S)-aminomethyl-2-tetrahydrofuran according to the proceduredescribed for Example 4B. ¹H NMR (CDCl₃, 300 MHz) δ 1.52-1.61 (m, 3H),1.70-1.79 (m, 1H), 1.87-2.06 (m, 2H), 2.13-2.27 (m, 2H), 2.49 (dd,J=18.3, 14.6 Hz, 1H), 3.21-3.49 (m, 2H), 3.64-3.72 (m, 1H), 3.74-3.82(m, 1H), 3.84-3.91 (m, 1H), 3.95-4.07 (m, 1H), 4.83-4.88 (m, 1H),5.12-5.13 (m, 1H), 6.25-6.31 (m, 1H), 7.34-7.40 (m, 1H), 7.53-7.61 (m,2H), 12.61 (br s, 1H); MS (ESI⁺) m/z 499 (M+H)⁺. Anal. calcd. forC₂₃H₂₂F₄N₂O₄S: C, 55.42; H, 4.45; N, 5.62. Found: C, 55.13; H, 4.25; N,5.62.

Example 152-fluoro-N-[3-(2-furoyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl]-6-(trifluoromethyl)benzamideExample 15A(2-amino-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-3-yl)(2-furyl)methanone

The title compound was prepared from commercially available3-(furan-2-yl)-3-oxopropanenitrile and Example 1A according to theprocedure described for Example 1B.

LC/MS (ESI⁺) m/z 276 (M+H)⁺.

Example 15B2-fluoro-N-[3-(2-furoyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl]-6-(trifluoromethyl)benzamide

The title compound was prepared from the product of Example 15A andcommercially available 2-fluoro-6-trifluoromethyl-benzoyl chlorideaccording to the procedure described for Example 1C. ¹H NMR (CDCl₃, 300MHz) δ 1.63-1.71 (m, 1H), 2.13-2.17 m, 4H), 3.26 (dd, J=16.3, 5.1 Hz,1H), 4.71 (dd, J=4.9, 4.9 Hz, 1H), 5.14-5.15 (m, 1H), 6.58-6.60 (m, 1H),7.16-7.17 (m, 1H), 7.35-7.41 (m, 1H), 7.55-7.64 (m, 3H), 11.13 (br s,1H); MS (ESI⁺) m/z 466 (M+H)⁺.

Example 16N-[3-(cyclobutylcarbonyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl]-N′-(1,1-dimethylpropyl)urea

To a 20-mL scintillation vial containing a magnetic stir bar were addedthe product from Example 8A (263 mg, 1.00 mmol), anhydroustetrahydrofuran (8 mL), and triethylamine (354 mg, 488 μL, 3.50 mmol),followed by drop-wise addition of a solution of triphosgene (0.35 mmol)in anhydrous tetrahydrofuran (2 mL). The resulting mixture was stirredat room temperature for 2 hours. A 2-mL aliquot of the mixture wasremoved and placed in a separate scintillation vial containing amagnetic stir bar and neat 2-methylbutan-2-amine (87 mg, 1.00 mmol) wasadded. The resulting mixture was stirred at room temperature overnight.The solvent and volatiles were removed by rotary evaporatory and theproduct was purified by flash chromatography (silica gel: 25% ethylacetate, 75% hexanes—product R_(f)˜0.3) to give 42 mg (56%) of the titlecompound. ¹H NMR (DMSO-d₆, 300 MHz) δ 0.79 (t, J=7.4 Hz, 3H), 1.22 (s,3H), 1.23 (s, 3H), 1.54-2.30 (m, 12H), 3.13-3.20 (m, 2H), 3.67-3.77 (m,1H), 4.67-4.70 (m, 1H), 4.95-4.97 (m, 1H), 7.68 (s, 1H), 11.39 (br s,1H); MS (ESI⁺) m/z 377 (M+H)⁺. Anal. calcd. for C₂₀H₂₈N₂O₃S: C, 63.80;H, 7.50; N, 7.50. Found: C, 63.65; H, 7.86; N, 7.37.

Example 17N-[3-(cyclobutylcarbonyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl]-N′-cyclopentylurea

The title compound was prepared from Example 8A) and commerciallyavailable cyclopentylamine according to the procedure described forExample 16. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.39-1.68 (m, 8H), 1.76-2.28 (m,10H), 3.14-3.23 (m, 2H), 3.68-3.78 (m, 1H), 3.88-3.99 (m, 1H), 4.68-4.71(m, 1H), 4.97-4.99 (m, 1H), 7.96 (d, J=4.4 Hz, 1H), 11.47 (br s, 1H); MS(ESI⁺) m/z 375 (M+H)⁺. Anal. calcd. for C₂₀H₂₆N₂O₃S: C, 64.14; H, 7.00;N, 7.48. Found: C, 63.99; H, 7.29; N, 7.20.

Example 18N-[3-(cyclobutylcarbonyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl]-N′-(1,2,2-trimethylpropyl)urea

The title compound was prepared from Example 8A and commerciallyavailable 3,3-dimethylbutan-2-amine according to the procedure describedfor Example 16. ¹H NMR (DMSO-d₆, 300 MHz) δ 0.87 (s, 9H), 0.99-1.02 (m,3H), 1.59-2.31 (m, 11H), 3.13-3.22 (m, 1H), 3.51-3.61 (m, 1H), 3.68-3.78(m, 1H), 4.66-4.70 (m, 1H), 4.97-4.98 (m, 1H), 7.77 (d, J=9.2 Hz, 1H),11.44 (br s, 1H); MS (ESI⁺) m/z 391 (M+H)⁺. Anal. calcd. forC₂₁H₃₀N₂O₃S: C, 64.58;; H, 7.74; N, 7.17. Found: C, 64.32; H, 8.06; N,6.94.

Example 19 ethyl2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thiophene-3-carboxylateExample 19A ethyl2-amino-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thiophene-3-carboxylateStep A

To a solution of 8-oxabicyclo[3.2.1]oct-6-en-2-one (3.38 g, 27.2 mmol)(prepared as described in Vogel, et al. Tetrahedron 1993, 49 (8),1649-1664) in 50 mL of ethanol was added Pd/C (10 wt %, 0.34 g). Thereaction flask was evacuated and flushed with nitrogen three times. Thena hydrogen balloon was added and the reaction flask was evacuated andflushed with hydrogen three times. The mixture was stirred under anatmosphere of hydrogen at ambient temperature for 16 hours. The mixturewas warmed to 45° C. and allowed to stir for 4 hours. The mixture wascooled to ambient temperature, evacuated and back-filled with nitrogenthree times, filtered, and concentrated under reduced pressure.Purification by chromatography (SiO₂, 50% hexanes in ethyl acetate)provided approximately 1:1.5 mixture of the starting material and thetitle compound.

Step B

To a mixture of the product from Step A (1.19 g, ˜9.6 mmol) in 20 mL ofethanol was added ethylcyanoacetate (1.12 mL, 10.5 mmol) and sulfur(0.34 g, 10.5 mmol). To this mixture was added morpholine (1.25 mL, 14.4mmol) drop-wise via syringe. The mixture was warmed to 60° C. and wasallowed to stir for 72 hours. The mixture was cooled to ambienttemperature, filtered, and concentrated under reduced pressure. Theresulting residue was purified on silica gel column chromatography(SiO₂, 50% hexanes in ethyl acetate).

Step C

A mixture of the product from Step B (1.37 g, ˜5.4 mmol) in ethanol (60mL) was shaken with 2.6 g Pd/C (5 wt %) under hydrogen (60 psi) andambient temperature for 30 hours. The mixture was filtered andconcentrated under reduced pressure. Purification by columnchromatography (SiO₂, 50% hexanes in ethyl acetate) provided the titlecompound (1.21 g, 4.8 mmol, ˜88% yield). MS (DCI/NH3) m/z 254 (M+H)⁺.

Example 19B ethyl2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thiophene-3-carboxylate

To a solution of the product of Example 19A (0.32 g, 1.26 mmol) andpyridine (0.41 mL, 5.1 mmol) in CH₃CN (10 mL) was added2-fluoro-6-(trifluoromethyl)-benzoylchloride (0.29 mL, 1.9 mmol). Themixture was warmed to 60° C. and was allowed to stir for 18 hours. Themixture was cooled to ambient temperature, quenched with saturatedaqueous NH₄Cl and diluted with CH₂Cl₂ (10 mL). The layers were separatedand the aqueous layer was extracted with three 5-mL portions of CH₂Cl₂.The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, concentrated under reduced pressure. Purification by columnchromatography (SiO₂, 60% hexanes in ethyl acetate) provided the titlecompound (0.38 g, 0.86 mmol, 68% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (t, J=7.1 Hz, 3H), 1.67-1.78 (m, 1H), 2.07-2.30 (m, 3H), 2.42 (dd,J=15.9, 0.7 Hz, 1H), 3.30 (dd, J=16.1, 4.9 Hz, 1H), 4.32 (q, J=7.1 Hz,2H), 4.77-4.85 (m, 1H), 5.50 (d, J=5.1 Hz, 1H), 7.36-7.44 (m, 1H),7.54-7.64 (m, 2H), 11.49 (s, 1H); MS (DCI/NH₃) m/z 461 (M+H)⁺; Anal.calculated for C₂₀H₁₂F₄NO₄S: Calc: C, 54.17; H, 3.86; N, 3.16; Found: C,54.08; H, 3.80; N, 3.13.

Example 20N-[3-(cyclobutylcarbonyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thien-2-yl]-N′-(1,2-dimethylpropyl)urea

The title compound was prepared from the product of Example 8A andcommercially available racemic 3-methylbutan-2-amine according to theprocedure described for Example 16. ¹H NMR (DMSO-d₆, 300 MHz) δ0.84-0.88 (m, 6H), 1.01 (d, J=6.8 Hz, 3H), 1.59-2.28 (m, 11H), 3.14-3.21(m, 2H), 3.51-3.58 (m, 1H), 3.68-3.78 (m, 1H), 4.67-4.71 (m, 1H),4.97-4.99 (m, 1H), 7.82 (d, J=8.5 Hz, 1H), 11.47 (br s, 1H); MS (ESI⁺)m/z 377 (M+H)⁺.

Example 21 ethyl2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thiophene-3-carboxylateExample 21A hexahydro-2,5-methanopentalene-3a(1H)-carbonyl chloride

A solution of noradamantane carboxylic acid (0.25 g, 1.5 mmol) in 5 mLof thionyl chloride was warmed to reflux for 2 hours then cooled toambient temperature and concentrated under reduced pressure. The residuewas diluted with toluene (5 mL) then concentrated under reduced pressure(3×) to afford the title compound.

Example 21B ethyl2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thiophene-3-carboxylate

To the product of Example 19A (0.35 g, 1.4 mmol) in CH₃CN (7 mL) wasadded pyridine (0.34 mL, 4.1 mmol) followed by a solution of the productof Example 21A (1.5 mmol) in CH₃CN (7 mL) via cannula. This mixture waswarmed to reflux and was allowed to stir for 4 hours. The reactionmixture was cooled to 70° C. and was stirred for 16 hours. The materialwas cooled to ambient temperature, quenched with saturated aqueous NH₄Cland diluted with 10 mL of CH₂Cl₂. The layers were separated and theaqueous layer was extracted three 5-mL portions of CH₂Cl₂. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. Purification by columnchromatography (SiO₂, 60% hexanes in ethyl acetate) afforded the titlecompound (0.43 g, 1.07 mmol, 76% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm1.39 (t, J=7.1 Hz, 3H), 1.62-1.75 (m, 5H), 1.83-2.25 (m, 9H), 2.33-2.43(m, 3H), 2.74-2.81 (m, 1H), 3.26 (dd, J=15.8, 4.9 Hz, 1H), 4.35 (q,J=7.1 Hz, 2H), 4.74-4.82 (m, 1H), 5.49 (d, J=5.1 Hz, 1H), 11.38 (s, 1H);MS (DCI/NH₃) m/z 402 (M+H)⁺; Anal. calculated for C₂₂H₂₂F₄NO₄S: Calc: C,65.81; H, 6.78; N, 3.49; Found: C, 65.85; H, 6.87; N, 3.53.

Example 22N-{3-[(3,3-difluoroazetidin-1-yl)carbonyl]-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thien-2-yl}-2-fluoro-6-(trifluoromethyl)benzamideExample 22A2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thiophene-3-carboxylicacid

To a solution of the product of Example 19B (0.36 g, 0.81 mmol) inethanol (10 mL) was added 40 wt % aqueous KOH (2 mL). This mixture waswarmed to reflux for 3 hours, then cooled to ambient temperature andacidified to pH 1 with 1 N aqueous HCl. The mixture was extracted withthree 10-mL portions of ethyl acetate and the combined organic extractswere dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to provide the title compound (0.34 g, 0.81 mmol). MS(DCI/NH₃) m/z 416 (M+H)⁺, 433 (M+NH₄)⁺.

Example 22BN-{3-[(3,3-difluoroazetidin-1-yl)carbonyl]-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thien-2-yl}-2-fluoro-6-(trifluoromethyl)benzamide

To a solution of the product of Example 22A (0.11 g, 0.27 mmol) anddiisopropylethylamine (0.1 mL, 0.57 mmol) in tetrahydrofuran (5 mL) wasadded 3,3-difluoroazetidine hydrochloride (36 mg, 0.29 mmol) followed byO-(7-azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (HATU, 0.11 g, 0.29 mmol). The mixture was stirredat ambient temperature for 4 hours, quenched with saturated aqueousNaHCO₃ (5 mL) and diluted with ethyl acetate (5 mL). The layers wereseparated and the aqueous layer was extracted with three 5-mL portionsof ethyl acetate. The combined organic extracts were dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure.Purification by column chromatography (SiO₂, 50% hexanes in ethylacetate) afforded the title compound (56 mg, 0.11 mmol, 42% yield). ¹HNMR (300 MHz, CDCl₃) δ ppm 1.71-1.82 (m, 1H), 1.97-2.03 (m, 1H),2.09-2.29 (m, 2H), 2.48 (d, J=16.6 Hz, 1H), 3.28 (dd, J=16.1, 4.9 Hz,1H), 4.30-4.59 (m, 4H), 4.80-4.86 (m, 1H), 5.10 (d, J=5.4 Hz, 1H),7.37-7.45 (m, 1H), 7.55-7.65 (m, 2H), 10.08 (s, 1H); MS (DCI/NH₃) m/z491 (M+H)⁺, 508 (M+NH₄)⁺; Anal. calculated for C₂₁H₁₆F₆N₂O₃S: Calc: C,51.43; H, 3.29; N, 5.71; Found: C, 51.80; H, 3.63; N, 5.43.

Example 232-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-N-propyl-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thiophene-3-carboxamide

The product of Example 22A (0.11 g, 0.265 mmol), propylamine (51 μL,0.29 mmol), diisopropylethylamine (0.1 mL, 0.56 mmol) andO-(7-azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (0.11 g, 0.28 mmol) in tetrahydrofuran (5 mL) wereprocessed as described in Example 22B to provide the title compound (45mg, 0.10 mmol, 37% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 0.98 (t, J=7.3Hz, 3H), 1.57-1.66 (m, 2H), 1.78-1.90 (m, 1H), 2.08-2.17 (m, 1H),2.18-2.40 (m, 2H), 2.47 (d, J=15.9 Hz, 1H), 3.27-3.45 (m, 3H), 4.80-4.89(m, 1H), 5.25 (d, J=5.4 Hz, 1H), 5.45 (s, 1H), 7.31-7.42 (m, 1H),7.51-7.62 (m, 2H), 12.18 (s, 1H); MS (DCI/NH₃) m/z 457 (M+H)⁺, 474(M+NH₄)⁺; Anal. calculated for C₂₁H₂₀F₄N₂O₃S: Calc: C, 55.26; H, 4.42;N, 6.14; Found: C, 55.19; H, 4.15; N, 5.97.

Example 24N-{3-[(3,3-difluoroazetidin-1-yl)carbonyl]-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thien-2-yl}hexahydro-2,5-methanopentalene-3a(1H)-carboxamideExample 24A2-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thiophene-3-carboxylicacid

The product of Example 21B (0.41 g, 1.02 mmol) and KOH (3 mL of a 40%aqueous solution) in ethanol (7 mL) were processed as in Example 22A toprovide the title compound (0.38 g, 1.02 mmol, 100% yield). MS (DCI/NH₃)m/z 374 (M+H)⁺, 391 (M+NH₄)⁺.

Example 24BN-{3-[(3,3-difluoroazetidin-1-yl)carbonyl]-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thien-2-yl}hexahydro-2,5-methanopentalene-3a(1H)-carboxamide

The product of Example 24A (0.11 g, 0.29 mmol), 3,3-difluoroazetidinehydrochloride (41 mg, 0.32 mmol), diisopropylethylamine (0.11 mL, 0.65mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (0.12 g, 0.31 mmol) in tetrahydrofuran (5 mL) wereprocessed as described in Example 22B to provide the title compound (88mg, 0.20 mmol, 67% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.59-1.76 (m,5H), 1.83-2.02 (m, 5H), 2.06-2.23 (m, 4H), 2.37-2.48 (m, 3H), 2.72-2.79(m, 1H), 3.24 (dd, J=16.1, 4.9 Hz, 1H), 4.37 (q, J=11.6 Hz, 2H), 4.55(q, J=11.9 Hz, 2H), 4.77-4.83 (m, 1H), 5.12 (d, J=5.8 Hz, 1H), 10.19 (s,1H); MS (DCI/NH₃) m/z 449 (M+H)⁺ , 466 (M+NH ₄)⁺; Anal. calculated forC₂₃H₂₆F₂N₂O₃S: Calc: C, 61.59; H, 5.84; N, 6.25; Found: C, 61.42; H,5.57; N, 6.17.

Example 25 ethyl2-[({[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy}carbonyl)amino]-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate

To a 20-mL scintillation vial containing a magnetic stir bar were addedthe product of Example 1B 203 mg, 0.800 mmol), anhydrous tetrhdyrofuran(8 mL), and triethylamine (446 μL, 3.20 mmol), followed by addition of asolution of triphosgene (95.0 mg, 0.320 mmol) in dry tetrahydrofuran (1mL). The reaction mixture was allowed to stir at room temperature for 2hours. (−)-menthol (156 mg, 1.00 mmol) was added and the resulting brownslurry was stirred at room temperature overnight. Water (10 mL) wasadded and the mixture was extracted with dichloromethane (3×10 mL). Thecombined organic extracts were dried over magnesium sulfate, filtered,and concentrated by rotary evaporator. Purification by flashchormatogrpahy (silica gel: 10% ethyl acetate, 90% hexanes, productR_(f)-0.5) gave 261 mg (75%) of the title compound. ¹H NMR (DMSO-d₆, 300MHz) δ 0.76 (d, J=6.8 Hz, 3H), 0.85-0.91 m., 6H), 1.00-1.15 (m, 2H),1.29 (t, J=7.1 Hz, 3H), 1.38-1.69 (m, 6H), 1.83-2.11 (m, 6H), 3.02-3.09(m, 1H), 4.24 (q, J=6.9 Hz, 2H), 4.56-4.69 (m, 2H), 5.07 (br s, 1H),10.23 (br s, 1H); MS (ESI⁺) m/z 436 (M+H)⁺. Anal. calcd. for C₂₃H₃₃NO₅S:C, 63.42; H, 7.64; N, 3.22. Found: C, 64.22; H, 7.50; N, 2.66.

Example 26 ethyl2-{[5-chloro-2-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate

The title compound was prepared from the product of Example 1B andcommercially available 5-chloro-2-(trifluoromethyl)benzoyl chlorideaccording to the procedure described for Example 1C. ¹H NMR (DMSO-d₆,300 MHz) δ 1.28 (t, J=7.1 Hz, 3H), 1.58-1.69 (m, 1H), 1.98-2.14 (m, 2H),2.55-2.61 (m, 1H), 3.06-3.14 (m, 2H), 4.24 (q, J=7.1 Hz, 2H), 4.68-4.72(m, 1H), 5.14 (br s, 1H), 7.83-7.98 (m, 3H), 11.38 (br s, 1H); MS (ESI⁺)m/z 460 (M+H)⁺. Anal. calcd. for C₂₀H₁₇ClF₃NO₅S: C, 52.24; H, 3.73; N,3.05. Found: C, 52.35; H, 3.36; N, 2.92.

Example 27 ethyl2-{[3-chloro-2-fluoro-6-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate

The title compound was prepared from the product of Example 1B andcommercially available 3-chloro-2-fluoro-6-(trifluoromethyl)benzoylchloride according to the procedure described for Example 1C. ¹H NMR(DMSO-d₆, 300 MHz) δ 1.26 (t, J=7.1 Hz, 3H), 1.60-1.70 (m, 1H),1.98-2.14 (m, 3H), 2.57 (D, J=16.6 Hz, 1H), 3.06-3.13 (m, 1H), 4.22 (q,J=7.1 Hz, 2H), 4.68-4.72 (m, 1H), 5.13-5.15 (m, 1H), 7.77 (d, J=9.0 Hz,1H), 8.01 (dd, J=8.0, 8.0 Hz, 1H), 11.58 (br s, 1H); MS (ESI⁺) m/z 478(M+H)⁺. Anal. calcd. for C₂₀H₁₆ClF₄NO₄S: C, 50.27; H, 3.37; N, 2.93.Found: C, 50.64; H, 3.07; N, 2.83.

Example 282-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-propyl-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thiophene-3-carboxamide

The product of Example 24A (0.115 g, 0.31 mmol), propylamine (60 μL,0.34 mmol), diisopropylethylamine (0.12 mL, 0.68 mmol) andO-(7-azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (0.12 g, 0.32 mmol) in tetrahydrofuran (6 mL) wereprocessed as described in Example 22B to provide the title compound (70mg, 0.17 mmol, 55% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 0.96-1.05 (m,3H), 1.59-1.71 (m, 6H), 1.74-1.96 (m, 5H), 2.04-2.17 (m, 3H), 2.19-2.33(m, 2H), 2.37 (s, 2H), 2.42 (d, J=15.9 Hz, 1H), 2.76 (t, J=6.6 Hz, 1H),3.29 (dd, J=15.9, 4.7 Hz, 1H), 3.35-3.49 (m, 2H), 4.78-4.84 (m, 1H),5.24 (d, J=5.4 Hz, 1H), 5.38 (t, J=5.1 Hz, 1H), 12.02 (s, 1H); MS(DCI/NH₃) m/z 415 (M+H)⁺, 432 (M+NH₄)⁺; Anal. calculated forC₂₃H₃₀N₂O₃S: Calc: C, 66.64; H, 7.29; N, 6.76; Found: C, 66.57; H, 7.43;N, 6.74.

Example 292-[(hexahydro-2,5-methanopentalen-3a(1H)-ylcarbonyl)amino]-N-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thiophene-3-carboxamide

The product of Example 24A (70 mg, 0.19 mmol),3,3,3-trifluoropropylamine hydrochloride (Oakwood Products, 31 mg, 0.21mmol), diisopropylethylamine (72 μL, 0.41 mmol) andO-(7-azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (75 mg, 0.20 mmol) in tetrahydrofuran (5 mL) wereprocessed as described in Example 22B to provide the title compound (65mg, 0.14 mmol, 73% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.62-1.82 (m,5H), 1.85-1.98 (m, 4H), 2.01-2.34 (m, 5H), 2.33-2.55 (m, 5H), 2.73-2.81(m, 1H), 3.29 (dd, J=16.1, 4.6 Hz, 1H), 3.69-3.81 (m, 2H), 4.77-4.86 (m,1H), 5.21 (d, J=5.8 Hz, 1H), 5.66 (t, J=6.4 Hz, 1H), 11.96 (s, 1H); MS(DCI/NH₃) m/z 469 (M+H)⁺, 486 (M+NH₄)⁺; Anal. calculated forC₂₃H₂₇F₃N₂O₃S: Calc: C, 58.96; H, 5.81; N, 5.98; Found: C, 59.14; H,5.83; N, 5.85.

Example 30 ethyl2-[(isoquinolin-1-ylcarbonyl)amino]-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate

The title compound was prepared from the product of Example 1B andisoquinoline-1-carbonyl chloride (prepared from commercially availableisoquinoline-1-carboxylic acid and thionyl chloride) according to theprocedure described for Example 1C. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.39 (t,J=7.1 Hz, 3H), 1.63-1.72 (m, 1H), 1.99-2.16 (m, 3H), 2.64 (d, J=17.3 Hz,1H), 3.12-3.19 (m, 1H), 4.36 (q, J=7.1 Hz, 2H), 4.71-4.75 (m, 1H),5.16-5.18 (m, 1H), 7.83-7.94 (m, 2H), 8.14-8.17 (m, 1H), 8.24 (d, J=5.4Hz, 1H), 8.73 (d, J=5.4 Hz, 1H), 9.52 (d, J=8.1 Hz, 1H), 13.17 (br s,1H); MS (ESI⁺) m/z 409 (M+H)⁺. Anal. calcd. for C₂₂H₂₀N₂O₄S: C, 64.69;H, 4.94; N, 6.83. Found: C, 65.01; H, 4.77; N, 6.59.

Example 312-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-N-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide

The title compound was prepared from the product of Example 4A andcommercially available 3,3,3-trifluoropropylamine according to theprocedure described for Example 4B. MS (DCI/NH₃) m/z 511 (M+H)⁺.

Example 32N-ethyl-2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide

The title compound was prepared from the product of Example 4A andethylamine according to the procedure described for Example 4B. MS(DCI/NH₃) m/z 443 (M+H)⁺.

Example 33N-cyclopentyl-2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thiophene-3-carboxamide

The product of Example 22A (0.10 g, 0.24 mmol), cyclopentylamine (26 μL,0.26 mmol), diisopropylethylamine (92 μL, 0.53 mmol) andO-(7-azabenzotriazole-1-yl)-N, N,N′N′-tetramethyluroniumhexafluorophosphate (96 mg, 0.25 mmol) in 7 mL tetrahydrofuran wereprocessed as described in Example 22B to provide the title compound (52mg, 0.11 mmol, 45% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.41-1.52 (m,2H), 1.65-1.74 (m, 4 H), 1.79-1.90 (m, 1H), 1.96-2.39 (m, 5H), 2.47 (d,J=16.3 Hz, 1H), 3.33 (dd, J=16.3, 4.7 Hz, 1H), 4.26-4.37 (m, 1H),4.81-4.87 (m, 1H), 5.22 (d, J=5.4 Hz, 1H), 5.37-5.42 (m, 1 H), 7.31-7.41(m, 1H), 7.52-7.59 (m, 2H), 12.18 (s, 1H); MS (DCI/NH₃) m/z 483 (M+H)⁺,500 (M+NH₄)⁺; Anal. calculated for C₂₃H₂₂F₄N₂O₃S: Calc: C, 57.25; H,4.60; N, 5.81; Found: C, 57.24; H, 4.42; N, 5.72.

Example 34 propyl2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylateExample 34A propyl2-amino-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate

The title compound was prepared from propyl cyanoacetate and the productof Example 1A using the procedure described for Example 1B. LC/MS (ESI⁺)m/z 268 (M+H)⁺.

Example 34B propyl2-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate

The title compound was prepared from the product of Example 34A andcommercially available 2-fluoro-6-trifluoromethyl-benzoyl chlorideaccording to the procedure described for Example 1C. ¹H NMR (DMSO-d₆,300 MHz) δ0.92 (t, J=7.1 Hz, 3H), 1.60-1.72 (m, 3H), 1.98-2.17 (m, 3H),2.57 (d, J=17.0 Hz, 1H), 3.10 (dd, J=17.1, 4.9 Hz, 1H), 4.15 (t, J=6.4Hz, 2H), 4.69-4.73 (m, 1H), 5.14-5.16 (m, 1H), 7.73-7.87 (m, 3H), 11.53(br s, 1H); MS (ESI⁺) m/z 458 (M+H)⁺. Anal. calcd. for C₂₁H₁₉F₄NO₄S: C,55.14; H, 4.19; N, 3.06. Found: C, 55.19; H, 3.99; N, 3.08.

Example 352-{[2-fluoro-6-(trifluoromethyl)benzoyl]amino}-N,N-dimethyl-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxamide

The title compound was prepared from the product of Example 4A anddimethylamine according to the procedure described for Example 4B. MS(DCI/NH₃) m/z 443 (M+H)⁺.

Example 36N-{3-[(3-methoxyazetidin-1-yl)carbonyl]-5,6,7,8-tetrahydro-4H-4,7-epoxycyclohepta[b]thien-2-yl}hexahydro-2,5-methanopentalene-3a(1H)-carboxamide

The product of Example 24A (0.11 g, 0.29 mmol), 3-methoxy-azetidinehydrochloride (40 mg, 0.32 mmol), diisopropylethylamine (0.11 mL, 0.65mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (0.12 g, 0.31 mmol) in tetrahydrofuran (5 mL) wereprocessed as described in Example 22B to provide the title compound (72mg, 0.16 mmol, 56% yield). ¹H NMR (300 MHz, CD₃OD) δ ppm 1.36-1.39 (m,2H), 1.66-1.77 (m, 3H), 1.85-2.23 (m, 7H), 2.37 (s, 2H), 2.47 (d, J=15.9Hz, 1H), 2.69-2.76 (m, 1H), 3.14-3.24 (m, 4H), 3.83-3.88 (m, 2H),3.88-3.99 (m, 2H), 4.21-4.34 (m, 3H), 4.74-4.82 (m, 1H), 5.09 (d, J=5.4Hz, 1H); MS (DCI/NH₃) m/z 443 (M+H)⁺, 460 (M+NH₄)⁺; Anal. calculated forC₂₄H₃₀N₂O₄S.0.3H₂O: Calc: C, 64.35; H, 6.88; N, 6.25; Found: C, 64.06;H, 6.81; N, 6.16.

Example 37 ethyl2-[({[(1R,2S,5R)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyl]oxy}-carbonyl)amino]-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate

The title compound was prepared from the product of Example 1B and(−)-8-phenylmenthol according to the procedure described for Example 25.MS (ESI) m/z 512 (M+H)⁺.

Example 38 propyl2-{[2-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate

The title compound was prepared from the product of Example 34A andcommercially available 2-trifluoromethyl-benzoyl chloride according tothe procedure described for Example 1C. ¹H NMR (DMSO-d₆, 300 MHz) δ 0.92(t, J=7.5 Hz, 3H), 1.64-1.71 (m, 3H), 1.98-2.15 (m, 3H), 2.58 (d, J=17.0Hz, 1H), 3.11 (dd, J=16.6, 4.4 Hz, 1H), 4.16 (t, J=6.4 Hz, 2H),4.69-4.74 (m, 1H), 5.14-5.16 (m, 1H), 7.80-7.94 (m, 4H), 11.40 (br s,1H); MS (ESI⁺) m/z 440 (M+H)⁺. Anal. calcd. for C₂₁H₂₀F₃NO₄S: C, 57.40;H, 4.59; N, 3.19. Found: C, 57.44; H, 4.47; N, 3.14.

Example 39 ethyl2-{[2-(trifluoromethyl)benzoyl]amino}-5,6,7,8-tetrahydro-4H-5,8-epoxycyclohepta[b]thiophene-3-carboxylate

The title compound was prepared from the product of Example 1B andcommercially available 2-trifluoromethylbenzoyl chloride according tothe procedure described for Example 1C. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.27(t, J=7.1 Hz, 3H), 1.59-1.69 (m, 1H), 1.98-2.17 (m, 3H), 2.58 (d, J=17.0Hz, 1H), 3.11 (dd, J=17.1, 4.9 Hz, 1H), 4.24 (q, J=6.9 Hz, 2H),4.68-4.73 (m, 1H), 5.13-5.15 (m, 1H), 7.78-7.94 (m, 4H), 11.38 (br s,1H); MS (ESI⁺) m/z 426 (M+H)⁺. Anal. calcd. for C₂₀H₁₈F₃NO₄S: C, 56.46;H, 4.26; N, 3.29. Found: C, 56.78; H, 4.18; N, 3.30.

Biological Data In Vitro Methods

The CB₁ and CB₂ radioligand binding assays described herein are utilizedto determine the selectivity of compounds of the present invention forbinding to CB₂ relative to CB₁ receptors.

Human CB₂ Radioligand Binding Assays:

HEK293 cells stably expressing human CB₂ receptors were grown until aconfluent monolayer was formed. Briefly, the cells were harvested andhomogenized in TE buffer (50 mM Tris-HCl, 1 mM MgCl₂, and 1 mM EDTA)using a polytron for 2×10 second bursts in the presence of proteaseinhibitors, followed by centrifugation at 45,000×g for 20 minutes. Thefinal membrane pellet was re-homogenized in storage buffer (50 mMTris-HCl, 1 mM MgCl₂, and 1 mM EDTA and 10% sucrose) and frozen at −78°C. until used. Saturation binding reactions were initiated by theaddition of membrane preparation (protein concentration of 5 μg/well forhuman CB₂) into wells of a deep well plate containing ([³H]CP-55,940(120 Ci/mmol, a nonselective CB agonist commercially available fromTocris) in assay buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl₂, and 0.5mg/mL fatty acid free BSA, pH 7.4). After 90 min incubation at 30° C.,binding reaction was terminated by the addition of 300 μL/well of coldassay buffer followed by rapid vacuum filtration through a UniFilter-96GF/C filter plates (pre-soaked in 1 mg/mL BSA for 2 hours). The boundactivity was counted in a TopCount using Microscint-20. Saturationexperiments were conducted with twelve concentrations of [³H]CP-55,940ranging from 0.01 to 8 nM. Competition experiments were conducted with0.5 nM [³H]CP-55,940 and five concentrations (1 nM to 10 μM) ofdisplacing ligands. The addition of 10 μM unlabeled CP-55,940 (Tocris,Ellisville, Mo.) was used to assess nonspecific binding.

Representative compounds of the present invention bound to CB₂ receptorswith a K_(i) of less than 1,000 nM, preferably less than 400 nM, morepreferably less than 200 nM and, most preferably less than 100 nM.

Human CB₁ Radioligand Binding Assay:

HEK293 human CB₁ membranes were purchased from Perkin Elmer. Binding wasinitiated by the addition of membranes (8-12 μg per well) into wells(Scienceware 96-well DeepWell plate, VWR, West Chester, Pa.) containing[³H]CP-55,940 (120 Ci/mmol, Perkin Elmer, Boston, Mass.) and asufficient volume of assay buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl₂,and 0.5 mg/mL fatty acid free BSA, pH 7.4) to bring the total volume to250 μL. After incubation (30° C. for 90 minutes), binding was terminatedby the addition of 300 μL per well of cold assay buffer and rapid vacuumfiltration (FilterMate Cell Harvester, Perkin Elmer, Boston, Mass.)through a UniFilter-96 GF/C filter plate (Perkin Elmer, Boston, Mass.)(pre-soaked in 0.3% PEI at least 3 hours), followed by five washes withcold assay buffer. The bound activity was counted in the TopCount usingMicroscint-20 (both from Perkin Elmer, Boston, Mass.). Competitionexperiments were conducted with 1 nM [³H]CP-55,940 and fiveconcentrations (1 nM to 10 μM) of displacing ligands. The addition of 10μM unlabeled CP-55,940 (Tocris, Ellisville, Mo.) was used to assessnonspecific binding. Representative compounds of the present inventionexhibited 10-folds to 1000-folds weaker binding affinity (higher K_(i))to CB₁ receptors than to CB₂ receptors.

These results show that the compounds of the present invention bindpreferably to CB₂ receptors, and therefore are selective ligands for theCB₂ receptor.

In Vivo Methods: Animals

Adult male Sprague-Dawley rats (250-300 g body weight, Charles RiverLaboratories, Portage, Mich.) were used. Animal handling andexperimental protocols were approved by the Institutional Animal Careand Use Committee (IACUC) at Abbott Laboratories. For all surgicalprocedures, animals were maintained under isoflurane anesthesia (4-5% toinduce, 1-3% to maintain), and the incision sites were sterilized usinga 10% povidone-iodine solution prior to and after surgeries.

Incisional Model of Postoperative Pain

A skin incision model of postoperative pain was produced using theprocedures described in Brennan et al., 1996, Pain, 64, 493. All ratswere anesthetized with isoflurane delivered via a nose cone. Right hindpaw incision was performed following sterilization procedures. Theplantar aspect of the left hind paw was placed through a hole in asterile plastic drape. A 1-cm longitudinal incision was made through theskin and fascia of the plantar aspect of the hind paw, starting 0.5 cmfrom the proximal edge of the heel and extending towards the toes, theplantar muscle was elevated and incised longitudinally leaving themuscle origin and insertion points intact. The skin was then closed withtwo mattress sutures (5-0 nylon). After surgery, animals were thenallowed to recover for 2 hours, at which time tactile allodynia wasassessed as described below. To evaluate the anti-nociceptive effects,animals were i.p. administered vehicle or test compound 90 minutesfollowing skin incision and tactile allodynia was assessed 30 minutesafter compound administration.

Tactile allodynia was measured using calibrated von Frey filaments(Stoelting, Wood Dale, Ill.) as described in Chaplan, S. R., F. W. Bach,J. W. Pogrel, J. M. Chung, and T. L. Yaksh, 1994, Quantitativeassessment of tactile allodynia in the rat paw, J. Neurosci. Methods,53, 55. Rats were placed into inverted individual plastic cage(20×12.5×20 cm) on top of a suspended wire mesh grid, and acclimated tothe test chambers for 20 minutes. The von Frey filaments were appliedperpendicularly from underneath the cage through openings in the wiremesh floor directly to an area within 1-3 mm (immediately adjacent) ofthe incision, and then held in this position for approximately 8 secondswith enough force to cause a slight bend in the filament. Positiveresponses included an abrupt withdrawal of the hind paw from thestimulus, or flinching behavior immediately following removal of thestimulus. A 50% withdrawal threshold was determined using an up-downprocedure (Dixon, W. J., 1980, Efficient Analysis of ExperimentalObservations, Ann. Rev. Pharmocol. Toxicol., 20, p. 441).

Representative compounds of the present invention showed a statisticallysignificant change in paw withdrawal latency versus a saline vehicle atless than about 300 micromoles/kg in the incisional model ofpostoperative pain. In a more preferred embodiment, compounds of thepresent invention showed efficacy at less than about 50 micromoles/kg inthe incisional model of postoperative pain.

Spinal Nerve Ligation Model of Neuropathic Pain

A model of spinal nerve ligation-induced (SNL model) neuropathic pain asoriginally described by Kim and Chung (Kim, S. H. and J. M. Chung, 1992,Pain, 50, 355) was used to evaluate the compounds of the presentinvention. The left L5 and L6 spinal nerves of the rat were isolatedadjacent to the vertebral column and tightly ligated with a 5-0 silksuture distal to the dorsal root ganglia, and care was taken to avoidinjury of the L4 spinal nerve. Sham rats underwent the same procedure,but without nerve ligation. All animals were allowed to recover for atleast one week and not more than three weeks prior to assessment oftactile allodynia.

Tactile allodynia was measured using calibrated von Frey filaments(Stoelting, Wood Dale, Ill.) as described in Chaplan, S. R., F. W. Bach,J. W. Pogrel, J. M. Chung, and T. L. Yaksh, 1994, Quantitativeassessment of tactile allodynia in the rat paw, J. Neurosci. Methods,53, 55. Rats were placed into inverted individual plastic containers(20×12.5×20 cm) on top of a suspended wire mesh grid, and acclimated tothe test chambers for 20 minutes. The von Frey filaments were presentedperpendicularly to the plantar surface of the selected hind paw, andthen hold in this position for approximately 8 sec with enough force tocause a slight bend in the filament. Positive responses included anabrupt withdrawal of the hind paw from the stimulus, or flinchingbehavior immediately following removal of the stimulus. A 50% withdrawalthreshold was determined using an up-down procedure (Dixon, W. J., 1980,Efficient Analysis of Experimental Observations, Ann. Rev. Pharmocol.Toxicol., 20, p. 441). Only rats with a baseline threshold score of lessthat 4.25 g were used in this study, and animals demonstrating motordeficit were excluded. Tactile allodynia thresholds were also assessedin several control groups, including naive, sham-operated, and salineinfused animals a well as in the contralateral paws of nerve-injuredrats.

Representative compounds of the present invention showed a statisticallysignificant change in paw withdrawal latency versus a saline vehicle atless than about 300 micromoles/kg in the spinal nerve ligation model ofneuropathic pain. In a more preferred embodiment, compounds of thepresent invention showed efficacy at less than about 50 micromoles/kg inthe spinal nerve ligation model of neuropathic pain.

In addition to the data contained herein, several lines of evidencesupport the assertion that CB₂ receptors play a role in analgesia. Forexample, Zimmer et al. have reported that the nonselective cannabinoidagonist Δ⁹-THC retains some analgesic efficacy in CB₁ receptor knockoutmice (Zimmer, A., et al., Proc. Nat. Acad. Sci., 1999, 96, 5780-5785).HU-308 is one of the first highly selective CB₂ agonists identified thatelicits an antinociceptive response in the rat formalin model ofpersistent pain (Hanus, L., et al., Proc. Nat. Acad. Sci., 1999, 96,14228-14233). The CB₂-selective cannabiniod ligand AM-1241 exhibitsrobust analgesic efficacy in animal models of acute thermal pain (Malan,T. P., et al., Pain, 2001, 93, 239-245; Ibrahim, M. M., et al., Proc.Nat. Acad. Sci., 2005, 102(8), 3093-3098), persistent pain (Hohmann, A.G., et al., J. Pharmacol. Exp. Ther., 2004, 308, 446-453), inflammatorypain (Nackley, A. G., et al., Neuroscience, 2003, 119, 747-757;Quartilho, A. et al., Anesthesiology, 2003, 99, 955-60), and neuropathicpain (Ibrahim, M. M., et al., Proc. Nat. Acad. Sci., 2003, 100,10529-10533). The CB₂-selective partial agonist GW405833, also known asL768242, is efficacious in rodent models of neuropathic, incisional, andboth chronic and acute inflammatory pain (Valenzano, K. J., et al.,Neuropharmacology, 2005, 48, 658-672 and Clayton, N., et al., Pain,2002, 96, 253-260). The analgesic effects induced by these CB₂-selectiveligands are blocked by CB₂ and not by CB₁ receptor antagonists.Furthermore, at fully efficacious doses, AM-1241 and GW405833 are devoidof typical CB₁ receptor-mediated CNS side effects, providing evidencethat modulation of CB₂ receptors can produce broad-spectrum pain reliefwith reduced side-effect liability.

The potential exists for CB₂ modulators to have opioid sparing effects.A synergy between the analgesic effects of morphine and the nonselectiveCB agonist Δ⁹-THC has been documented (Cichewicz, D. L., Life Sci. 2004,74, 1317-1324). Therefore, CB₂ ligands have additive or synergisticanalgesic effects when used in combination with lower doses of morphineor other opioids, providing a strategy for reducing adverse opioidevents, such as tolerance, constipation, and respiratory depression,without sacrificing analgesic efficacy.

CB₂ receptors are present in tissues and cell types associated withimmune functions and CB₂ receptor mRNA is expressed by human B cells,natural killer cells, monocytes, neutrophils, and T cells (Galiegue etal., Eur. J. Biochem., 1995, 232, 54-61). Studies with CB₂ knockout micehave suggested a role for CB₂ receptors in modulating the immune system(Buckley, N. E., et al., Eur. J. Pharmacol. 2000, 396, 141-149).Although immune cell development and differentiation are similar inknockout and wild type animals, the immunosuppressive effects of Δ⁹-THCare absent in the CB₂ receptor knockout mice, providing evidence for theinvolvement of CB₂ receptors in immunomodulation. As such, selective CB₂modulators are useful for the treatment of autoimmune diseases includingbut not limited to multiple sclerosis, rheumatoid arthritis, systemiclupus, myasthenia gravis, type I diabetes, irritable bowel syndrome,psoriasis, psoriatic arthritis, and hepatitis; and immune relateddisorders including but not limited to tissue rejection in organtransplants, gluten-sensitive enteropathy (Celiac disease), asthma,chronic obstructive pulmonary disease, emphysema, bronchitis, acuterespiratory distress syndrome, allergies, allergic rhinitis, dermatitis,and Sjogren's syndrome.

Microglial cells are considered to be the immune cells of the centralnervous system (CNS) where they regulate the initiation and progressionof immune responses. They are quiescent and resting having a ramifiedmorphology as long as the CNS is healthy. Microglia expresses a varietyof receptors enabling them to survey the CNS and respond to pathologicalevents. Insult or injury to the CNS leads to microglial cell activation,which is characterized by various morphological changes allowingresponse to the lesion. Ramifications are retracted and microglia aretransformed into amoeboid-like cells with phagocytic function. They canproliferate, rapidly migrate to the site of injury, and produce andrelease cytokines, chemokines and complement components (Watkins L. R.,et al., Trends in Neuroscience, 2001, 24(8), 450; Kreutzberg, G. W.,Trends Neurosci., 1996, 19, 312-318). CB₂ receptor expression onmicroglia is dependent upon inflammatory state with higher levels of CB₂found in primed, proliferating, and migrating microglia relative toresting or fully activated microglial (Carlisle, S. J., et al. Int.Immunopharmacol., 2002, 2, 69). Neuroinflammation induces many changesin microglia cell morphology and there is an upregulation of CB₂receptors and other components of the endocannabinoid system. It isconceivable that CB₂ receptors may be more susceptible topharmacological effects during neuroinflammation (Walter, L., Stella,N., Br. J. Pharmacol. 2004, 141, 775-785). Neuroinflammation occurs inseveral neurodegenerative diseases, and induction of microglial CB₂receptors has been observed (Carrier, E. J., et al., Current DrugTargets—CNS & Neurological Disorders, 2005, 4, 657-665). Thus, CB₂ligands may be clinically useful for the treatment of neuroinflammation.

CB₂ receptor expression has been detected in perivascular microglialcells within normal, healthy human cerebellum (Nunez, E., et al.,Synapse, 2004, 58, 208-213). Perivascular cells are immunoregulatorycells located adjacent to CNS blood vessels and, along with parenchymalmicroglia and astrocytes, they play a pivotal role in maintaining CNShomeostasis and blood-brain barrier functionality (Williams, K., et al.,Glia, 2001, 36, 156-164). CB₂ receptor expression has also been detectedon cerebromicrovascular endothelial cells, which represent a maincomponent of the blood-brain barrier (Golech, S. A., et al., Mol. BrainRes., 2004, 132, 87-92). A recent report demonstrated that CB₂ receptorexpression is up-regulated in the brains of macaques with simianimmunodeficiency virus-induced encephalitis (Benito, C., et al., J.Neurosci. 2005, 25(10), 2530-2536). Thus, compounds that affect CB₂signaling may protect the blood-brain barrier and be clinically usefulin the treatment of neuroinflammation and a variety of neuroinflammatorydisorders including retroviral encephalitis, which occurs with humanimmunodeficiency virus (HIV) infection in the CNS.

Multiple sclerosis is common immune-mediated disease of the CNS in whichthe ability of neurons to conduct impulses becomes impaired throughdemyelination and axonal damage. The demyelination occurs as aconsequence of chronic inflammation and ultimately leads to a broadrange of clinical symptoms that fluctuate unpredictably and generallyworsen with age. These include painful muscle spasms, tremor, ataxia,motor weakness, sphincter dysfunction, and difficulty speaking (Pertwee,R. G., Pharmacol. Ther. 2002, 95, 165-174). The CB₂ receptor isup-regulated on activated microglial cells during experimentalautoimmune encephalomyelitis (EAE) (Maresz, K., et al., J. Neurochem.2005, 95, 437-445). CB₂ receptor activation prevents the recruitment ofinflammatory cells such as leukocytes into the CNS (Ni, X., et al.,Multiple Sclerosis, 2004, 10, 158-164) and plays a protective role inexperimental, progressive demyelination (Arevalo-Martin, A.; et al., J.Neurosci., 2003, 23(7), 2511-2516), which are critical features in thedevelopment of multiple sclerosis. Thus, CB₂ receptor modulators providea unique treatment for demyelinating pathologies.

Alzheimer's disease is a chronic neurodegenerative disorder accountingfor the most common form of elderly dementia. Recent studies haverevealed that CB₂ receptor expression is upregulated in neuriticplaque-associated microglia from brains of Alzheimer's disease patients(Benito, C., et al., J. Neurosci., 2003, 23(35), 11136-11141). In vitro,treatment with the CB₂ agonist JWH-133 abrogated β-amyloid-inducedmicroglial activation and neurotoxicity, effects that can be blocked bythe CB₂ antagonist SR144528 (Ramirez, B. G., et al., J. Neurosci. 2005,25(8), 1904-1913). CB₂ modulators possess both anti-inflammatory andneuroprotective actions and thus have clinical utility in treatingneuroinflammation and in providing neuroprotection associated with thedevelopment of Alzheimer's disease.

Increased levels of epithelial CB₂ receptor expression are observed inhuman inflammatory bowel disease tissue (Wright, K., et al.,Gastroenterology, 2005, 129, 437-453). Activation of CB₂ receptorsre-established normal gastrointestinal transit after endotoxicinflammation was induced in rats (Mathison, R., et al., Br. J.Pharmacol. 2004, 142, 1247-1254). CB₂ receptor activation in a humancolonic epithelial cell line inhibited TNF-α-induced interleukin-8(IL-8) release (Ihenetu, K. et al., Eur. J. Pharmacol. 2003, 458,207-215). Chemokines released from the epithelium, such as theneutrophil chemoattractant IL-8, are upregulated in inflammatory boweldisease (Warhurst, A. C., et al., Gut, 1998, 42, 208-213). Thus,administration of CB₂ receptor modulators represents a novel approachfor the treatment of inflammation and disorders of the gastrointestinaltract including but not limited to inflammatory bowel disease, irritablebowel syndrome, secretory diarrhea, ulcerative colitis, Crohn's diseaseand gastroesophageal reflux disease (GERD).

Hepatic fibrosis occurs as a response to chronic liver injury andultimately leads to cirrhosis, which is a major worldwide health issuedue to the severe accompanying complications of portal hypertension,liver failure, and hepatocellular carcinoma (Lotersztajn, S., et al.,Annu. Rev. Pharmacol. Toxicol., 2005, 45, 605-628). Although CB₂receptors were not detectable in normal human liver, CB₂ receptors wereexpressed liver biopsy specimens from patients with cirrhosis.Activation of CB₂ receptors in cultured hepatic myofibroblasts producedpotent antifibrogenic effects (Julien, B., et al., Gastroenterology,2005, 128, 742-755). In addition, CB₂ knockout mice developed enhancedliver fibrosis after chronic administration of carbon tetrachloriderelative to wild-type mice. Administration of CB₂ receptor modulatorsrepresents a unique approach for the treatment of liver fibrosis.

CB₂ receptors are involved in the neuroprotective and anti-inflammatorymechanisms induced by the interleukin-1 receptor antagonist (IL-1ra)(Molina-Holgado, F., et al., J. Neurosci., 2003, 23(16), 6470-6474).IL-1ra is an important anti-inflammatory cytokine that protects againstischemic, excitotoxic, and traumatic brain insults. CB₂ receptors play arole in mediating these neuroprotective effects indicating that CB₂ligands are useful in the treatment of traumatic brain injury, stroke,and in mitigating brain damage.

Cough is a dominant and persistent symptom of many inflammatory lungdiseases, including asthma, chronic obstructive pulmonary disease, viralinfections, and pulmonary fibrosis (Patel, H. J., et al., Brit. J.Pharmacol., 2003, 140, 261-268). Recent studies have provided evidencefor the existence of neuronal CB₂ receptors in the airways, and havedemonstrated a role for CB₂ receptor activation in cough suppression(Patel, H. J., et al., Brit. J. Pharmacol., 2003, 140, 261-268 andYoshihara, S., et al., Am. J. Respir. Crit. Care Med., 2004, 170,941-946). Both exogenous and endogenous cannabinoid ligands inhibit theactivation of C-fibers via CB₂ receptors and reduce neurogenicinflammatory reactions in airway tissues (Yoshihara, S., et al., J.Pharmacol. Sci. 2005, 98(1), 77-82; Yoshihara, S., et al., Allergy andImmunology, 2005, 138, 80-87). Thus, CB₂-selective modulators haveutility as antitussive agents for the treatment pulmonary inflammation,chronic cough, and a variety of airway inflammatory diseases includingbut not limited to asthma, chronic obstructive pulmonary disease, andpulmonary fibrosis.

Osteoporosis is a disease characterized by reduced bone mass, whichleads to deterioration of bone microstructure and increasedsusceptibility to fracture. Age is associated with bone loss and it isestimated that 50% of all Caucasian women will have osteoporosis by theage of 80 (Ralston, S. H., Curr. Opin. Pharmacol., 2003, 3, 286-290).There is a substantial genetic contribution to bone mass density and theCB₂ receptor gene is associated with human osteoporosis (Karsak, M., etal., Human Molecular Genetics, 2005, 14(22), 3389-3396). Osteoclasts andosteoblasts are largely responsible for maintaining bone structure andfunction through a process called remodeling, which involves resorptionand synthesis of bone (Boyle, W. J., et al., Nature, 2003, 423,337-342). CB₂ receptor expression has been detected on osteoclasts andosteoblastic precursor cells, and administration of a CB₂ agonist inmice caused a dose-dependent increase in bone formation (Grotenhermen,F. and Muller-Vahl, K., Expert Opin. Pharmacother., 2003, 4(12),2367-2371). Cannabinoid inverse agonists, including the CB₂-selectiveinverse agonist SR144528, have been shown to inhibit osteoclast activityand reverse ovariectomy-induced bone loss in mice, which is a model forpost-menopausal osteoporosis (Ralston, S. H., et al., Nature Medicine,2005, 11, 774-779). Thus, CB₂ modulators are useful for the treatmentand prevention of osteoporosis, osteoarthritis, and bone disorders.

Artherosclerosis is a chronic inflammatory disease and is a leadingcause of heart disease and stroke. CB₂ receptors have been detected inboth human and mouse atherosclerotic plaques. Administration of lowdoses of THC in apolipoprotein E knockout mice slowed the progression ofatherosclerotic lesions, and these effects were inhibited by theCB₂-selective antagonist SR144528 (Steffens, S., et al., Nature, 2005,434, 782-786). Thus, compounds with activity at the CB₂ receptor areclinically useful for the treatment of atheroscelorsis.

CB₂ receptors are expressed on malignant cells of the immune system andtargeting CB₂ receptors to induce apoptosis may constitute a novelapproach to treating malignancies of the immune system. Selective CB₂agonists induce regression of malignant gliomas (Sanchez, C., et al.,Cancer Res., 2001, 61, 5784-5789), skin carcinomas (Casanova, M. L., etal., J. Clin. Invest., 2003, 111, 43-50), and lymphomas (McKallip, R.J., et al., Blood, 2002, 15(2), 637-634). Thus, CB₂ modulators haveutility as anticancer agents against tumors of immune origin.

Activation of CB₂ receptors has been demonstrated to protect the heartagainst the deleterious effects of ischemia and reperfusion (Lepicier,P., et al., Brit. J. Pharm. 2003, 139, 805-815; Bouchard, J.-F., et al.,Life Sci. 2003, 72, 1859-1870; Filippo, C. D., et al., J. Leukoc. Biol.2004, 75, 453-459). Thus, CB₂ modulators have utility for the treatmentor prophylaxis of cardiovascular disease and the development ofmyocardial infarction.

The present invention also provides pharmaceutical compositions thatcomprise compounds of the present invention. The pharmaceuticalcompositions comprise compounds of the present invention orpharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, topically (as by powders, ointments ordrops), bucally or as an oral or nasal spray. The term “parenterally” asused herein, refers to modes of administration that include intravenous,intramuscular, intraperitoneal, intrasternal, subcutaneous andintraarticular injection and infusion.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such as propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), vegetable oils (such as olive oil), injectableorganic esters (such as ethyl oleate) and suitable mixtures thereof.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents, which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions, which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable carrier or excipient, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals that are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether. Methods to form liposomes are known in the art. See, forexample, Prescott, Ed., Methods in Cell Biology, Volume XIV, AcademicPress, New York, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compoundmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants, which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the present invention can be employedin pure form or, where such forms exist, in pharmaceutically acceptablesalt, ester or prodrug form. The phrase “therapeutically effectiveamount” of the compound of the invention means a sufficient amount ofthe compound to treat disorders, at a reasonable benefit/risk ratioapplicable to any medical treatment. It will be understood, however,that the total daily usage of the compounds and compositions of thepresent invention will be decided by the attending physician within thescope of sound medical judgement. The specific therapeutically effectivedose level for any particular patient will depend upon a variety offactors including the disorder being treated and the severity of thedisorder; activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed; and like factors well known in the medical arts.

The term “pharmaceutically acceptable salt” as used herein, means saltsderived from inorganic or organic acids. The salts can be prepared insitu during the final isolation and purification of compounds of Formula(I) or separately by reacting the free base of a compound of Formula (I)with an inorganic or organic acid. Representative acid addition saltsinclude, but are not limited to, acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, malate,maleate, fumarate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, sulfate, (L) tartrate, (D) tartrate,(DL) tartrate, thiocyanate, phosphate, glutamate, bicarbonate,p-toluenesulfonate, and undecanoate.

The term “pharmaceutically acceptable prodrug” or “prodrug,” as usedherein, represents those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like.Prodrugs of the present invention may be rapidly transformed in vivo tocompounds of Formula (I), for example, by hydrolysis in blood.

The present invention contemplates compounds of Formula (I) formed bysynthetic means or formed by in vivo biotransformation.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms, such as hemi-hydrates. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water and ethanol among others, are equivalent to the unsolvatedforms for the purposes of the invention.

The total daily dose of the compounds of this invention administered toa human or lower animal may range from about 0.003 to about 30mg/kg/day. For purposes of oral administration, more preferable dosescan be in the range of from about 0.01 to about 10 mg/kg/day. Ifdesired, the effective daily dose can be divided into multiple doses forpurposes of administration; consequently, single dose compositions maycontain such amounts or submultiples thereof to make up the daily dose.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof.

1-26. (canceled)
 27. A method for treating a disorder selected from the group consisting of inflammatory disorders, immune disorders, neurological disorders, cancers of the immune system, respiratory disorders, and cardiovascular disorders in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I)

or a pharmaceutically suitable salt or prodrug thereof, wherein

is absent or is a bond; m, n are each independently 0, 1 or 2; p is 1 or 2; q and r are each independently 0 or 1; s is 0, 1, 2, 3, or 4; R₁ is selected from the group consisting of alkyl, alkoxyalkyl, alkylcarbonyl, cyano, cyanoalkyl, halo, haloalkyl, R₄O₂C—, R_(c)R_(d)NC(O)—, and R_(c)R_(d)NS(O)₂—; R₂ is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, —O(R_(h)), and R_(e)R_(f)N—; R₃ is selected from the group consisting of alkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, R₅—C(O)—, R₅—C(═N—OR_(p))—, R₆OC(O)—, R_(g)R_(j)NC(O)—, R₅—S(O)₂—, and R_(g)R_(j)NS(O)₂—; R₄ is selected from the group consisting of alkyl, arylalkyl, haloalkyl, heteroarylalkyl, and heterocyclealkyl; R₅, at each occurrence, is selected from the group consisting of alkyl, alkoxyalkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, and heterocycle; R₆ is selected from the group consisting of alkyl, arylalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclealkyl, and heteroarylalkyl; R_(c) and R_(d), at each occurrence, are each independently selected from the group consisting of hydrogen and alkyl, or R_(c) and R_(d) together with the nitrogen atom to which they are attached form a heterocyclic ring; R_(e) is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; R_(f) is selected from the group consisting of hydrogen and alkyl; R_(g), at each occurrence, is independently selected from the group consisting of hydrogen, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, heteroarylalkyl, heterocyclealkyl, and heterocyclealkyl; R_(j), at each occurrence is independently selected from the group consisting of hydrogen, alkyl, and haloalkyl; R_(h) is a cycloalkyl ring optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, haloalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, and heterocyclealkyl; and R_(p) is selected from the group consisting of hydrogen and alkyl.
 28. (canceled) 